Nitric oxide (NO) plays a critical role in a wide range of bodily functions, including vasodilation, neurotransmission, wound healing, suppression of platelet activation, and modulation of ciliary beat frequency. Further, inhaled gas phase NO is now routinely used to treat neonatal pulmonary hypertension. In infection, NO released by neutrophils and macrophages functions as a potent antimicrobial/antiviral agent, and low nM concentrations of NO efficiently disperse biofilm formed by a variety of bacterial strains. Recent clinical trials have demonstrated its benefit in treating a variety of airway infections. In contrast, traditional antibiotics exhibit reduced efficacy against established bacteria colonies, i.e., biofilms, and when used within a catheter lock solution they do not mitigate other catheter dysfunction problems, including thrombotic complications related to platelet activation along the outer surface of the catheter. Thus, the combined antimicrobial and antithrombotic properties of NO make it an ideal candidate to prevent catheter-related blood stream infections (CRBSI) and thrombotic complications for end stage renal disease (ESRD) patients with tunneled dialysis catheters (TDCs). Recently, it has been shown that stabilized forms of NO, S-nitrosothiols (RSNOs), are a convenient way to deliver therapeutic levels of NO for some of these medical applications. NOTA Laboratories now proposes to use RSNO chemistry to develop two related disposable insert device variants for use with TDCs that are capable of releasing significant NO fluxes for 3-4 days. One device variant would be a catheter insert cap that bathes the extracorporeal portion, above the pinch clamp (the hub area) of a TDC, to deliver bactericidal levels of NO in the catheter region most prone to bacterial intrusion. The second product variant would be a longer insert that would extend to the distal tip and release NO through the entire length of the TDC. These devices would consist of an appropriate narrow diameter polymeric tube packed with the RSNO in a hydratable matrix. After each dialysis session the lumens of the TDC will be filled with saline lock solution and the devices will be inserted into both lumens where they will spontaneously generate NO until the next dialysis session, typically 3 days. If the TDC is composed of a NO permeable material, fibrin sheath formation on the outer surface of the TDC should also be suppressed. Phase I research will focus on three aims: 1) identifying the optimal RSNO chemistry and tubing to make the device; 2) evaluating the NO release of the inserts within dual-lumen medical-grade TDC tubing; and 3) demonstrating the antimicrobial activity of optimized disinfection inserts on the inner and outer surfaces of TDC catheter tubing.
Public Health Relevance Statement: NARRATIVE End Stage Renal Disease Dialysis (ESRD), i.e., kidney failure, is a significant health problem in the United States and is commonly treated with hemodialysis (HD) either by use of a surgically constructed shunt, or by use of a tunneled dialysis central venous catheter (TDC). However, widely used TDCs are associated with decreased patient survival due to multiple complications including central venous stenosis, as well as high rates of infection and thrombosis, requiring an average of 2.0 hospitalizations per patient year (with 25% being infection related). NOTA Laboratories now plans to develop a new product line of disinfection devices that consist of a tube packed with a dry reagent formulation containing a S-nitrosothiol (RSNO), along with appropriate additives, that when inserted into the lumens of TDCs (with lock solution within) is activated to release nitric oxide (NO), a potent bactericidal and anti-thrombotic agent, for up to 4 days. NO, a gas, disperses throughout the catheter lumens, preventing bacterial colonization inside the catheter and furthermore permeates the walls of the catheter (not possible with antibiotics) to serve as a localized antimicrobial and anti-thrombotic (anti-platelet activation) agent on the outer surfaces of the TDC.
Project Terms: Acetylcysteine; Adhesions; Aftercare; Antibiotics; Anticoagulants; antimicrobial; Antiviral Agents; aqueous; Area; Ascorbic Acid; Bacteremia; Bacteria; Bacterial Counts; bactericide; Bioreactors; Blood; Caliber; cardiovascular infection; cardiovascular risk factor; Catheters; Cell Count; Cellulose; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chemicals; Chemistry; Chronic; Clinical Trials; Closure by clamp; Coagulation Process; Collaborations; cost; crystallinity; Cysteine; density; design; Devices; Dialysis patients; Dialysis procedure; Diffuse; Disinfectants; Disinfection; Distal; End stage renal failure; Esters; Exhibits; experimental study; Failure; Fibrin; Fibrinolytic Agents; Fistula; Fluorescent Dyes; follow-up; Formulation; Frequencies; Functional disorder; Gases; General Population; Glutathione; Health; Hemodialysis; Hospitalization; Hydration status; hydrophilicity; imaging modality; improved; Infection; Inhalation; Kidney Failure; Kinetics; Laboratories; Length; macrophage; Measures; Medical; Michigan; Microbial Biofilms; microbicide; Modeling; Molecular Weight; mortality; natural antimicrobial; neonatal pulmonary hypertension; neurotransmission; neutrophil; Nitric Oxide; Operative Surgical Procedures; particle; Patients; Penicillamine; Permeability; Phase; Platelet Activation; Play; Polyethylene Glycols; Polymers; Polyurethanes; Polyvinyl Alcohol; prevent; Property; prospective; Pseudomonas aeruginosa; Reagent; Research; Role; S-nitro-N-acetylpenicillamine; S-Nitrosothiols; Saline; Sepsis; Shunt Device; Silicone Elastomers; Slide; Stainless Steel; Stains; Staphylococcus aureus; Stenosis; Stream; Surface; Testing; Therapeutic; Thrombosis; Thrombus; Time; Treatment Cost; treatment duration; Tube; United States; Variant; Vasodilation; Venous; Water; Wound Healing; Zinc Oxide
