Vascular Response of a Polymer-Free Paclitaxel-Coated Stent (Zilver PTX) versus a Polymer-Coated Paclitaxel-Eluting Stent (Eluvia) in Healthy Swine Femoropopliteal Arteries.

PURPOSE: To compare the long-term vascular healing responses of healthy swine iliofemoral arteries treated with a polymer-free paclitaxel-eluting stent (Z-PES, Zilver PTX) or a fluoropolymer-based paclitaxel-eluting stent (FP-PES, Eluvia). MATERIALS AND METHODS: Bilateral iliofemoral arteries in 20 swine were treated with a Z-PES (n = 16) or a FP-PES (n = 24) and were examined histologically at 1, 3, 6, and 12 months. RESULTS: Morphometric analysis revealed larger external and internal elastic lamina, stent expansion, and lumen area in the FP-PES than in the Z-PES at all timepoints. Luminal narrowing was similar in the 2 groups at 1 month; however, greater stenosis was observed in the Z-PES group at 3 months, with significant regression thereafter, resulting in equivalent stenosis at 6 and 12 months. Greater drug effect and less complete vessel healing were found in the FP-PES group at all timepoints, including greater numbers of malapposed struts with excessive fibrin deposition at 1 and 3 months, than in the Z-PES group. Three of 12 FP-PESs from the 6- and 12-month cohorts also showed circumferential medial disruption with peri-strut inflammation, whereas no abnormal findings were observed in contralateral Z-PESs. CONCLUSIONS: Prolonged paclitaxel release with the presence of a permanent polymer may contribute to the differential vascular responses seen for the Z-PES and FP-PES groups, including medial layer disruption and aneurysmal vessel degeneration that was sometimes observed in the FP-PES group. These distinct features should be confirmed by pathology and in vivo imaging of human superficial femoral arteries to determine their clinical significance.

Catheter-based retrograde coronary sinus infusion is a practical delivery technique for introducing biological molecules into the cardiac system.

OBJECTIVES: To demonstrate coronary sinus (CS) retrograde catheterization as a practicable technique for delivering biologics into the heart. BACKGROUND: There are many options to deliver biologics into the heart. However, there is no single optimal technique when considering safety, biologic retention, and reproducibility. Retrograde delivery has the potential to address many of these concerns. This study evaluated retrograde CS infusion of luciferase-expressing plasmid in a porcine model using the Advance® CS Coronary Sinus Infusion Catheter and bioluminescence imaging to track the expression of the infused biological markers. METHODS: Plasmid was delivered retrograde into the CS in one of three infusion volumes. Twenty-four hours post-infusion, hearts were excised and underwent bioluminescence imaging to characterize the expression of the infusates. Heart and lung biopsies were also assessed for luciferase expression using RT-qPCR. RESULTS: Retrograde infusion was safe and successful in all nine test subjects. Luciferase detection was inconsistent in the low volume group. Bioluminescence was confined predominantly along the posterolateral left ventricle for medium volume infusions and was more broadly dispersed along the anterior side of the heart for high volume infusions. Tissue mRNA analysis corroborated the bioluminescence results, with the highest concentration of luciferase expression localized in the left ventricle. CONCLUSIONS: Retrograde CS infusion is a promising technique for delivering biological molecules to the heart. Specifically, this study demonstrated that the low pressure coronary venous system accommodates a wide range of infusion volumes and that biological infusates can be maintained in situ following the resumption of coronary venous flow.

Biologic Drug Effect and Particulate Embolization of Drug-Eluting Stents versus Drug-Coated Balloons in Healthy Swine Femoropopliteal Arteries.

PURPOSE: To compare the drug effect in treated vessels and downstream effects in distal skeletal muscle of drug-coated balloons (DCBs) and drug-eluting stents (DESs) in a healthy preclinical swine model. MATERIALS AND METHODS: Four groups of treated iliofemoral arteries (percutaneous transluminal angioplasty [PTA]+DES, DCB+DES, DCB+bare metal stent [BMS], and DCB alone) of 12 healthy swine were assessed, with euthanasia at 30 days. Biological drug effect was evaluated using smooth muscle cell (SMC) loss score according to both depth and circumference as well as a neointimal fibrin and medial proteoglycan scores which were compared between the 4 groups. Vascular and skeletal muscle changes in regions downstream from the treated site were also assessed histologically for evidence of emboli. RESULTS: DESs showed greater medial SMC loss in the treated arteries irrespective of preceding DCB or PTA treatment in terms of depth (DCB+DES vs PTA+DES vs DCB+BMS vs DCB alone; median, 4.0 mm vs 3.8 mm vs 3.0 mm vs 2.2 mm; P = .009) and circumference (4.0 mm vs 3.5 mm vs 2.0 mm vs 1.2 mm, respectively; P = .007). Sections of skeletal muscles downstream from the treated arteries showed arteriolar changes of fibrinoid necrosis consistent with paclitaxel effect exclusively in the DCB groups (DCB+BMS, 26.9% of sections; DCB+DES, 14.3%; DCB alone, 19.2%; PTA+DES, 0%; P = .02). CONCLUSIONS: In the treated arteries, irrespective of preceding DCB treatment or PTA, DES treatment showed maximum drug effects vs DCB alone or in combination with BMS placement, and there was no detrimental toxic effect in DCB-treated iliofemoral arteries before DES treatment compared with PTA before DES treatment. Downstream vascular changes were exclusively seen in groups treated with DCBs.

Safety of Zilver PTX Drug-Eluting Stent Implantation Following Drug-Coated Balloon Dilation in a Healthy Swine Model.

PURPOSE: To compare the safety of Zilver PTX drug-eluting stents (DES) following drug-coated balloon (DCB) angioplasty or conventional balloon angioplasty (BA) in a healthy porcine iliofemoral artery model. METHODS: DES implantation following DCB (DCB+DES) or BA (BA+DES) was assessed by angiography and histology in the nondiseased iliofemoral arteries of 20 animals, with sacrifice at 1, 3, and 6 months. Safety assessment compared quantitative measures of vessel integrity (eg, preservation of artery geometry, structure, and lumen dimensions; absence of aneurysm; malapposition) and histological parameters (eg, excessive inflammation). The percentage of uncovered struts could not be >30% per section and the endothelial cell loss had to be <50%. The vascular and skeletal muscle changes in the downstream regions were also assessed histologically for evidence of emboli. RESULTS: No significant differences in safety parameters, including inflammation and endothelial cell loss, were observed between the 2 groups at all time points. Percentage of fibrin was significantly higher in DCB+DES at 3 months [20.0% (IQR 11.6, 28.4) vs BA+DES 4.2% (IQR 1.4, 9.6), respectively; p=0.04], with consistent trends between groups at all time points. Medial smooth muscle cell loss peaked at 1 month and was not statistically different between groups at any time point, although the loss was greater in the DCB+DES group. Sections with arterioles exhibiting paclitaxel-associated fibrinoid necrosis in downstream tissues were observed exclusively in the DCB group at 1 month (14.3% of sections) and 3 months (11.5%). CONCLUSION: This preclinical study suggests that Zilver PTX stent implantation is a safe strategy after DCB angioplasty and might be considered for patients who require stenting after DCB treatment.

MK-801 administration during neonatal ethanol withdrawal attenuates interpositus cell loss and juvenile eyeblink conditioning deficits.

Binge-level doses of ethanol have been demonstrated to severely disrupt the cerebellum and cerebellum-dependent tasks when administered to rodent subjects during the early postnatal period. N-methyl-d-aspartic acid (NMDA) receptor-mediated excitotoxicity associated with ethanol withdrawal has been implicated as a significant component contributing to neurotoxic effects resulting from early ethanol exposure, and studies using MK-801 (dizocilpine) have reported protection from ethanol-induced damage. The present study examined whether the administration of MK-801 during ethanol withdrawal would ameliorate ethanol-associated cell death in the interpositus nucleus of the cerebellum and behavioral deficits in a cerebellar dependent task. Long Evans rat pups were treated with ethanol (5.25 g/kg) in a binge-like manner on postnatal day 6 using intragastric intubation. Subjects then received an injection of MK-801 (0.5mg/kg) or vehicle during withdrawal, 30h after ethanol exposure. Rats were then trained on an eyeblink classical conditioning task as juveniles (40 days of age), and cerebellar interpositus nucleus numbers were assessed after conditioning. Ethanol-exposed subjects exhibited reductions in neuronal populations and behavioral deficits during eyeblink conditioning. However, MK-801 administration significantly attenuated observed deficiencies, suggesting a protective effect resulting from MK-801 treatment during ethanol withdrawal. These results support the role of NMDA receptor-mediated excitotoxicity as a component mechanism by which ethanol produces teratogenicity. Additionally, our findings support previous reports that have shown correlations between dependent measures of eyeblink classical-conditioning behavior and unbiased cell counts in the interpositus nucleus.

Neural regulation of ejaculation.

INTRODUCTION: Delineation of the underlying neurophysiological mechanisms of ejaculatory behavior is crucial for the treatment of male sexual dysfunction, including premature ejaculation. Recent studies provide compelling evidence that a population of lumbar spinothalamic (LSt) cells may play a role in the regulation of the ejaculatory response. Subsequent to ejaculation, LSt cells exhibit markers of activation that are not only highly correlated with ejaculatory behavior, but are also absent following the expression of other components of sexual behavior, such as mounts or intromissions. Similarly, targeted chemical lesion of LSt cells using substance P-saporin abolishes ejaculatory behavior explicitly. Early evidence suggests that pharmacological manipulation of LSt cells may offer additional evidence of crucial LSt cell involvement in the generation of ejaculation. AIM: This review is intended to summarize what has currently been revealed regarding the role of LSt cells in the regulation and generation of ejaculatory behavior, and also to discuss the direction of future behavioral investigations. METHODS: Information presented in this discussion was derived from analysis of numerous recent articles detailing the delineation of anatomical and physiological correlates of sexual behavior, as well as numerous literature searches using the National Library of Medicine PubMed Services. RESULTS: A great deal of the work that has led to the implication of LSt cells in ejaculatory behavior is reviewed in the present article, including clinical data, as well as anatomical, physiological, and behavioral examinations. The rationale for ongoing pharmacological studies is also discussed. CONCLUSION: LSt cells appear to play a vital role in the generation and regulation of ejaculatory behavior. Additional elucidation of this "ejaculation generator" could prove invaluable for the future treatment of male sexual dysfunction. Studies are currently in progress to further reveal the precise function of these cells and mechanisms of action through which they operate.