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.
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.
Intravenous administration of N-(β-alanyl-l-leucyl-l-alanyl-l-leucyl)doxorubicin (4) induces an acute toxic reaction, killing animals in a few minutes. This results from its positive charge at ...physiological pH combined with its propensity to form large aggregates in aqueous solutions. Negatively charged N-capped versions of 4 such as the succinyl derivative 5 can be administered by the iv route at more than 10 times the LD50 of doxorubicin without inducing the acute toxic reaction, and they are active in vivo.
Oligopeptidic derivatives of anthracyclines unable to penetrate cells were prepared and screened for their stability in human blood and their reactivation by peptidases secreted by cancer cells. ...N-beta-alanyl-L-leucyl-L-alanyl-L-leucyl-doxorubicin was selected as a new candidate prodrug. The NH2-terminal beta-alanine allows a very good blood stability. A two-step activation by peptidases found in conditioned media of cancer cells ultimately yields N-L-leucyl-doxorubicin. In vitro, when MCF-7/6 cancer cells are exposed to the prodrug, they accumulate about 14 times more doxorubicin than MRC-5 normal fibroblasts, whereas when exposed to doxorubicin the uptake is slightly higher in fibroblasts than in MCF-7/6 cells. This increased specificity of the prodrug over doxorubicin was confirmed in cytotoxicity assays using the same cell types. In vivo, the prodrug proved about nine times less toxic than doxorubicin in the normal mouse and also much more efficient in two different experimental chemotherapy models of human breast tumors.
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.
The nuclear envelope is a selective barrier against the movement of macromolecules between the nucleus and cytoplasm. Nuclear proteins larger than relative molecular mass 20,000-40,000 are probably ...actively transported across the envelope through the nuclear pore complex and are directed by specific nuclear location sequences (NLS) in the proteins. NLS mediate the nuclear import of isolated nuclear proteins after microinjection into whole cells and the nuclear accumulation of chimaeric proteins or of non-nuclear proteins conjugated to synthetic peptides. The best-characterized NLS is the simian virus 40 large T-antigen sequence. We have identified two proteins of rat liver by chemical cross-linking that interact with a synthetic peptide containing this sequence: this interaction is specific for a functional NLS, is saturable, and high affinity. The binding proteins are present in a post-mitochondrial supernatant, in nuclei and in a nuclear envelope fraction, which is consistent with a role in the transport of nuclear proteins from the cytoplasm to the nucleus.
Nucleoside phosphoramidates provide an elegant means to permit cellular absorption of masked phosphate esters, and, by doing so, remove any dependence of the biological response on nucleoside kinase ...activity. The present report details a means to synthesize nucleoside phophoramidates on a multipound scale with a high (>99%) degree of purity, suitable for use in human clinical trials.
Monocyte chemoattractant protein-1 (MCP-1) is a member of the β chemokine family which acts through specific seven transmembrane receptors to recruit monocytes, basophils, and T lymphocytes to sites ...of inflammation. To identify regions of the human MCP-1 protein which are important for its biological activity, we have synthesized domain-specific peptides and tested their ability to antagonize MCP-1 binding and chemotaxis in THP-1 cells. We have found that an intercysteine first loop peptide encompassing amino acids 13–35 inhibits MCP-1 binding and chemotactic activity, while peptides representing the amino-terminus (amino acids 1–10), second loop (amino acids 37–51), and carboxy-terminus (amino acids 56–71) of MCP-1 have no effect. In addition, we have found that cyclization of the first loop peptide by disulfide linkage and blocking the C-terminus of the peptide by amidation increases the activity of this peptide to block MCP-1 binding and chemotaxis. In order to specifically identify amino acid residues within the first loop that are crucial for MCP-1 functional activity, we have substituted alanine for tyrosine (Y13A) or arginine (R18A) in MCP-1 recombinant proteins. While baculovirus produced wild type and R18A MCP-1 proteins are indistinguishable in their ability to induce THP-1 chemotaxis and show modest effects in binding activity compared to commercially available recombinant MCP-1 protein, the Y13A point mutation causes a dramatic loss in function. The identification of functional domains of MCP-1 will assist in the design of MCP-1 receptor antagonists which may be clinically beneficial in a number of inflammatory diseases.
PDF
