DermaPort: A Novel Ported Vascular Access System for Hemodialysis.

Safe, ported access to the body for hemodialysis and other medical uses is increasingly necessary for modern medical therapy. Long-term hemodialysis offers unique challenges with its requirements for high blood flow, chronic implantation, and risks of infection. Although widely used, the polyester, cuffed, delete word and space hemodialysis catheter is far from ideal, and there is a need for an improved vascular access system to allow catheter adjustment and replacement, to reduce infections and to reduce medical costs. The DermaPort ported vascular access system (PVAS) was developed to meet this need. This report describes the design and testing of the PVAS port in vitro and in vivo. The results demonstrate that the system provides superior tissue integration coupled with infection-resisting slidability, allowing reposition and exchange of an indwelling catheter. Within 3 weeks, there was strong tissue ingrowth and establishment of a sterile barrier and over 13 weeks there was no evidence of infection or marsupialization. Additionally, an explanted PVAS sample from a 38 patient human clinical study showed the bulk of the metal mesh was associated with a macrophage-giant cell response and contained collagen and vascular elements. From these data, we conclude that the PVAS permitted stable ported access following a single stage implant procedure.

A Prospective Clinical Study of a Percutaneous Vascular Access System for Hemodialysis Catheters.

INTRODUCTION: Dysfunctional or infected hemodialysis polyester-cuffed catheters often require removal and are dissected out. The DermaPort™, percutaneous vascular access system (PVAS) permanently integrates a titanium mesh with the skin forming a stable, sterile barrier that allows for catheter placement, adjustment, or catheter exchange. This study aimed to describe the use and clinical outcomes of the DermaPort PVAS. METHODS: Thirty-eight patients who were receiving hemodialysis via a tunneled catheter were enrolled in this prospective open-label study. Assessments were performed biweekly for the first month and monthly thereafter, which included physical examination of the site of implantation for infection, catheter blood flow, and need for interventions to maintain catheter patency. Patient satisfaction was assessed with a visual analog score. RESULTS: Implantation of technical success was 100% with the implantation site demonstrating early tissue incorporation after 2 weeks and full incorporation within 4 weeks. The DermaPort™ successfully enabled 31 catheter exchanges and 10 repositions thru the port without dissection in 18 patients with nine repositions (90%) performed at bedside. The mean primary patency of the DermaPort™ was 172 ± 150 days, and mean secondary patency was 430 ± 203 days. There were no reportable serious adverse events in 12,100 catheter days of use and zero explantations of the device attributed to infection. The observed catheter infection rate was 0.33/1000 days. CONCLUSIONS: The DermaPort™ system can be effectively implanted and facilitates catheter interventions in hemodialysis patients requiring long-term catheter use and has a lower infection rate than historical catheter infection rates. Clinical Trial Protocol Number DermaPort-001 (no clinicaltrials.gov number as study was performed 9 years ago). Health Canada Reference Application Number: 118393.

NB2001, a novel antibacterial agent with broad-spectrum activity and enhanced potency against beta-lactamase-producing strains.

Enzyme-catalyzed therapeutic activation (ECTA) is a novel prodrug strategy to overcome drug resistance resulting from enzyme overexpression. beta-Lactamase overexpression is a common mechanism of bacterial resistance to beta-lactam antibiotics. We present here the results for one of the beta-lactamase ECTA compounds, NB2001, which consists of the antibacterial agent triclosan in a prodrug form with a cephalosporin scaffold. Unlike conventional beta-lactam antibiotics, where hydrolysis of the beta-lactam ring inactivates the antibiotic, hydrolysis of NB2001 by beta-lactamase releases triclosan. Evidence supporting the proposed mechanism is as follows. (i) NB2001 is a substrate for TEM-1 beta-lactamase, forming triclosan with a second-order rate constant (k(cat)/K(m)) of greater than 77,000 M-1 s-1. (ii) Triclosan is detected in NB2001-treated, beta-lactamase-producing Escherichia coli but not in E. coli that does not express beta-lactamase. (iii) NB2001 activity against beta-lactamase-producing E. coli is decreased in the presence of the beta-lactamase inhibitor clavulanic acid. NB2001 was similar to or more potent than reference antibiotics against clinical isolates of Staphylococcus aureus (including MRSA), Staphylococcus epidermidis, Streptococcus pneumoniae, vancomycin-resistant Enterococcus faecalis, Moraxella catarrhalis and Haemophilus influenzae. NB2001 is also active against Klebsiella pneumoniae, Enterobacter aerogenes, and Enterobacter cloacae. The results indicate that NB2001 is a potent, broad-spectrum antibacterial agent and demonstrate the potential of ECTA in overcoming beta-lactamase-mediated resistance.

CPI-0004Na, a new extracellularly tumor-activated prodrug of doxorubicin: in vivo toxicity, activity, and tissue distribution confirm tumor cell selectivity.

The search for cancer therapies that are more selective for tumor cells and spare normal sensitive cells has been very active for at least 20 years. The extracellularly tumor-activated peptidic prodrug of doxorubicin (Dox) CPI-0004Na (N-succinyl-beta-alanyl-L-leucyl-L-alanyl-L-leucyl-Dox) is potentially such a treatment. Here, we report the results of lethality studies performed with this compound in the mouse, showing that it is up to 4.6 times less toxic than Dox.HCl by the i.v. route and up to 16.2 times after i.p. administration. Pharmacokinetics and tissue distribution data indicate that this reduced toxicity is attributable to a lower uptake of Dox in normal tissues after treatment with CPI-0004Na than after the administration of an equimolar dose of Dox.HCl. For example, heart exposure to Dox is reduced >10-fold. Because of this reduced toxicity, higher doses of CPI-0004Na than of the parent drug could be used to treat nude mice bearing s.c. human breast (MCF-7/6) and colon (LS-174-T and CXF-280/10) tumors. In all three models, the prodrug showed a much improved efficacy as compared with Dox.HCl. Particularly, LS-174-T tumors that do not respond to Dox were inhibited by 68% after treatment with CPI-0004Na. Tissue distribution studies performed with MCF-7/6 tumor-bearing nude mice and comparing CPI-0004Na and Dox.HCl confirmed that the improved activity of the prodrug is actually the result of selective generation and uptake of Dox at the tumor site. Dox levels in tumor tissue were 2-fold higher after treatment with CPI-0004Na than after treatment with an equimolar dose of Dox.HCl, whereas normal tissue levels were reduced 1.4-29-fold.