By optimizing binding to a selected target protein, modern drug research strives to develop safe and efficacious agents for the treatment of disease. Selective drug action is intended to minimize undesirable side effects from scatter pharmacology. Celecoxib (Celebrex), valdecoxib (Bextra), and rofecoxib (Vioxx) are nonsteroidal antiinflammatory drugs (NSAIDs) due to selective inhibition of inducible cyclooxygenase COX-2 while sparing inhibition of constitutive COX-1. While rofecoxib contains a methyl sulfone constituent, celecoxib and valdecoxib possess an unsubstituted arylsulfonamide moiety. The latter group is common to many carbonic anhydrase (CA) inhibitors. Using enzyme kinetics and X-ray crystallography, we demonstrate an unexpected nanomolar affinity of the COX-2 specific arylsulfonamide-type celecoxib and valdecoxib for isoenzymes of the totally unrelated carbonic anhydrase (CA) family, such as CA I, II, IV, and IX, whereas the rofecoxib methyl sulfone-type has no effect. When administered orally to glaucomatous rabbits, celecoxib and valdecoxib lowered intraocular pressure, suggesting that these agents may have utility in the treatment of this disorder. The crystal structure of celecoxib in complex with CA II reveals part of this inhibition to be mediated via binding of the sulfonamide group to the catalytic zinc of CA II. To investigate the structural basis for cross-reactivity of these compounds between COX-2 and CA II, we compared the molecular recognition properties of both protein binding pockets in terms of local physicochemical similarities among binding site-exposed amino acids accommodating different portions of the drug molecules. Our approach Cavbase, implemented into Relibase, detects similarities between the sites, suggesting some potential to predict unexpected cross-reactivity of drugs among functionally unrelated target proteins. The observed cross-reactivity with CAs may also contribute to differences in the pharmacological profiles, in particular with respect to glaucoma and anticancer therapy and may suggest new opportunities of these COX-2 selective NSAIDs.

Magnetic particle imaging (MPI) is an emerging medical imaging modality which is based on the non-linear response of magnetic nanoparticles to an applied magnetic field. It is an important feature of MPI that even fast dynamic processes can be captured for 3D volumes. The high temporal resolution in turn leads to large amounts of data which have to be handled efficiently. But as the system matrix of MPI is non-sparse, the image reconstruction gets computationally demanding. Therefore, currently only basic image reconstruction methods such as Tikhonov regularization are used. However, Tikhonov regularization is known to oversmooth edges in the reconstructed image and to have only a limited noise reducing effect. In this work, we develop an efficient edge preserving and noise reducing reconstruction method for MPI. As regularization model, we propose to use the nonnegative fused lasso model, and we devise a discretization that is adapted to the acquisition geometry of the preclinical MPI scanner considered in this work. We develop a customized solver based on a generalized forward-backward scheme which is particularly suitable for the dense and not well-structured system matrices in MPI. Already a non-optimized prototype implementation processes a 3D volume within a few seconds so that processing several frames per second seems amenable. We demonstrate the improvement in reconstruction quality over the state-of-the-art method in an experimental medical setup for an in-vitro angioplasty of a stenosis.

Magnetic particle imaging (MPI) is a novel tracer-based in vivo imaging modality allowing quantitative measurements of the spatial distributions of superparamagnetic iron oxide (SPIO) nanoparticles in three dimensions (3D) and in real time using electromagnetic fields. However, MPI lacks the detection of morphological information which makes it difficult to unambiguously assign spatial SPIO distributions to actual organ structures. To compensate for this, a preclinical highly integrated hybrid system combining MPI and Magnetic Resonance Imaging (MRI) has been designed and gets characterized in this work. This hybrid MPI-MRI system offers a high grade of integration with respect to its hard- and software and enables sequential measurements of MPI and MRI within one seamless study and without the need for object repositioning. Therefore, time-resolved measurements of SPIO distributions acquired with MPI as well as morphological and functional information acquired with MRI can be combined with high spatial co-registration accuracy. With this initial phantom study, the feasibility of a highly integrated MPI-MRI hybrid systems has been proven successfully. This will enable dual-modal in vivo preclinical investigations of mice and rats with high confidence of success, offering the unique feature of precise MPI FOV planning on the basis of MRI data and vice versa.

Aims The aim of the study was to determine the incidence of oesophageal lesions after radiofrequency ablation (RFA) of atrial fibrillation (AF) with or without the use of oesophageal temperature probes. Methods and results Two hundred patients were prospectively randomized into two groups: the OPERA+ group underwent RFA using oesophageal probes (SensiTherm™); the OPERA− group received RFA using fixed energy levels of 25 W at the posterior wall without an oesophageal probe. All patients underwent post-interventional endoscopy and Holter-electrocardiogram after 6 months. (Clinical.Trials.gov: NCT03246594). One hundred patients were randomized in OPERA+ and 100 patients in OPERA−. The drop-out rate was 10%. In total, 18/180 (10%) patients developed endoscopically diagnosed oesophageal lesions (EDEL). There was no difference between the groups with 10/90 (11%) EDEL in OPERA+ vs. 8/90 (9%) in OPERA− (P = 0.62). Despite the higher power delivered at the posterior wall in OPERA+ [28 ± 4 vs. 25 ± 2 W (P = 0.001)], the average EDEL size was equal [5.7 ± 2.6 vs. 4.5 ± 1.7 mm (P = 0.38)]. The peak temperature did not correlate with EDEL size. During follow-up, no patient died. Only one patient in OPERA− required a specific therapy for treatment of the lesion. Cumulative AF recurrence after 6 (3–13) months was 28/87 (32%) vs. 34/88 (39%), P = 0.541. Conclusion This first randomized study demonstrates that intraoesophageal temperature monitoring using the SensiTherm™ probe does not affect the probability of developing EDEL. The peak temperature measured by the thermoprobe seems not to correlate with the incidence of EDEL. Empiric energy reduction at the posterior wall did not affect the efficacy of the procedure.