Preclinical pilot study monitoring topical drug penetration and dermal bioavailability of a peptidase inhibitor from different galenic formulations into pig dermis, using cutaneous microdialysis.

BACKGROUND: Cutaneous microdialysis (CM) is an ex vivo technique that allows study of tissue chemistry, including bioavailability of actual tissue concentration of unbound drug in the interstitial fluid of the body. AIM: To test the penetration and dermal bioavailability of galenic formulations of the small-molecule IP10.C8, a dual-protease inhibitor of the dipeptidyl peptidase and aminopeptidase families. METHODS: Using CM, we tested the penetration and dermal bioavailability of IP10.C8 into the dermis and subcutis of pigs, and determined the tissue concentration of IP10.C8 enzymatically, using an enzyme activity assay (substrate Gly-Pro-pNA) and high performance liquid chromatography. RESULTS: Dermal bioavailability was enhanced by using microemulsion or the addition of the penetration enhancer oleic acid to a hydroxyethylcellulose (HEC) gel formulation. Dermal bioavailability was also enhanced when galenic formulations were prepared with higher pH (7.5 vs. 6.5) or higher drug concentration (5% vs. 1%) in HEC gel. CONCLUSION: It seems possible, using CM for topical skin penetration testing in anaesthetized domestic pigs, to test the bioavailability of newly designed drugs. However, the experimental time is limited due to the anaesthesia, and is dependent on drug recovery. Validation of this technique for routine use is challenging, and more experiments are needed to validate this preclinical set-up.

Transcoronary pacing : Reliability during myocardial ischemia and after implantation of a coronary stent.

BACKGROUND: Transcoronary pacing is a useful therapeutic option for the treatment of unheralded bradycardias in the setting of percutaneous coronary interventions (PCI). OBJECTIVES: In the present study, we investigated the influence of stent implantation and transient myocardial ischemia on the feasibility of transcoronary pacing in a porcine model. METHODS: 7 adult pigs underwent a percutaneous coronary intervention with implantation of a coronary stent under general anaesthesia in an animal catheterization laboratory. Transcoronary pacing was established by using a standard guidewire isolated with an angioplasty balloon positioned in the periphery of the right coronary artery serving as the cathode. As the indifferent anode, a skin patch electrode at the back of the animal was used. The reliability of transcoronary pacing was assessed by measurement of threshold and impedance data and the magnitude of the epicardial electrogram at baseline, after implantation of a coronary stent and finally during myocardial ischemia. RESULTS: Effective transcoronary pacing could be demonstrated in all cases with the standard unipolar transcoronary pacing setup yielding a low pacing threshold at baseline of 1.3 ± 0.8 V with an impedance of 283 ± 67 Ω. Implantation of a coronary stent did not influence the pacing threshold (1.0 ± 0.4 V) and impedance (262 ± 63 Ω). Acute myocardial ischemia lead to a significant but clinically nonrelevant increase of the pacing threshold to 2.0 ± 0.6 V and a drop in pacing impedance (137 ± 39 Ω). CONCLUSIONS: Transcoronary pacing in the animal model is not affected by implantation of a coronary stent in the same vessel used for pacing. Despite a significant increase in pacing threshold, the transcoronary pacing approach is reliable in acute myocardial ischemia during a percutaneous coronary intervention.

The double guidewire approach for transcoronary pacing in a porcine model.

BACKGROUND: Transcoronary pacing is used for treatment of unheralded bradycardias in the setting of percutaneous coronary interventions (PCI). OBJECTIVES: In the present study we introduced a new concept - the double guidewire approach - for transcoronary pacing in a porcine model. METHODS: Transcoronary pacing was applied in 16 adult pigs under general anaesthesia in an animal catheterization laboratory. A special guidewire with electrical insulation by PTFE coating except for the distal part of the guidewire was positioned in the periphery of a coronary artery serving as the cathode. As the indifferent anode, an additional standard floppy tip guidewire was advanced into the proximal part of the same coronary vessel. The efficacy of double guidewire transcoronary pacing was assessed by measurement of threshold and impedance data and the magnitude of the epicardial electrogram compared with unipolar transcoronary pacing using a standard cutaneous patch electrode as indifferent anode. RESULTS: Transcoronary pacing was effective in all cases. Pacing thresholds obtained with the double guidewire technique (1.5 ± 0.9 V) were similar to those obtained by standard unipolar transcoronary pacing with a cutaneous patch electrode (1.2 ± 0.7 V) and unipolar transvenous pacing against the same cutaneous patch electrode (1.5 ± 1.0 V). Bipolar transvenous pacing yielded the lowest pacing threshold at 0.8 ± 0.4 V. CONCLUSIONS: Transcoronary pacing in the animal model with the novel "double guidewire approach" is a simple and effective pacing technique with comparable pacing thresholds obtained by standard unipolar transcoronary and transvenous pacing.

The importance of right atrial pacing electrode position and pacing configuration for intra-atrial and inter-atrial conduction times.

Pace prevention of atrial tachyarrhythmias is based in part on the reduction of intra-atrial (IAA) and/or inter-atrial (IEA) conduction. We previously introduced a novel pacing mode using floating atrial ring electrodes on a VDD-lead (BIdirectional MO nophasic impulSe: BIMOS). The effects of BIMOS pacing on IAA and IEA conduction times has not been studied. In nine Merino sheep electrode catheters were placed at the His-Bundle (HBE), high right atrium (HRA), coronary sinus ostium (Cs-Os), and left lateral atrium (LLA). A VDD-lead was introduced with floating electrodes in the high and mid right atrium (Floating). IAA (S/P-HRA, S/P-Cs-Os, S/P-HBE, S/P-Floating), IEA conduction times (S/P-LLA), and P-wave duration (PD) were measured during sinus rhythm (S), during bipolar cathodal pacing (P) in the HRA, in the Cs-Os position, as well as during BIMOS floating pacing. The mean PD during S was significantly shorter than during HRA- (66. 6+/-12.8ms; vs. 116.2+/-11.1ms; p<0.05) and Cs-Os-P (66.6+/-12.8ms vs. 94.4+/-9.0ms; p<0.05). In comparison to HRA-P, BIMOS configuration lead to a significant reduction of the P-wave duration (116.2+/-11.1ms vs. 85. 4+/-8.8ms; p<0.05). During BIMOS pacing, the global atrial conduction time was significantly shorter than during pacing in the HRA and Cs-Os position. The results of this study demonstrate a clear reduction of IAA and IEA conduction times using BIMOS configurations compared to conventional HRA-P. Furthermore, BIMOS pacing produced a more homogeneous atrial activation when compared with conventional HRA- and Cs-Os-P.

Short- and mid-term effects of irreversible electroporation on normal renal tissue: an animal model.

PURPOSE: Irreversible electroporation (IRE) is a novel nonthermal tissue ablation technique by high current application leading to apoptosis without affecting extracellular matrix. Previous results of renal IRE shall be supplemented by functional MRI and differentiated histological analysis of renal parenchyma in a chronic treatment setting. METHODS: Three swine were treated with two to three multifocal percutaneous IRE of the right kidney. MRI was performed before, 30 min (immediate-term), 7 days (short-term), and 28 days (mid-term) after IRE. A statistical analysis of the lesion surrounded renal parenchyma intensities was made to analyze functional differences depending on renal part, side and posttreatment time. Histological follow-up of cortex and medulla was performed after 28 days. RESULTS: A total of eight ablations were created. MRI showed no collateral damage of surrounded tissue. The highest visual contrast between lesions and normal parenchyma was obtained by T2-HR-SPIR-TSE-w sequence of DCE-MRI. Ablation zones showed inhomogeneous necroses with small perifocal edema in the short-term and sharp delimitable scars in the mid-term. MRI showed no significant differences between adjoined renal parenchyma around ablations and parenchyma of untreated kidney. Histological analysis demonstrated complete destruction of cortical glomeruli and tubules, while collecting ducts, renal calyxes, and pelvis of medulla were preserved. Adjoined kidney parenchyma around IRE lesions showed no qualitative differences to normal parenchyma of untreated kidney. CONCLUSIONS: This porcine IRE study reveals a multifocal renal ablation, while protecting surrounded renal parenchyma and collecting system over a mid-term period. That offers prevention of renal function ablating centrally located or multifocal renal masses.