The pleural cavity is the space between the exterior membrane of the lungs and the interior membrane of the body cavity containing the lungs. This space normally contains a small amount of liquid. In diseases such as pneumonia or tuberculosis, the membranes become inflamed and the pleural cavity can fill up with substantially more liquid, putting pressure on the lungs and causing a variety of symptoms, such as coughing, difficulty with breathing and fever. This occurs in as many as half of hospitalized pneumonia cases and may affect 1 million patients each year in the United States. Treatment often involves surgery, which can have significant complications, or multiple doses of a drug to reduce the inflammation and thickening of the membranes, which can be impractical. These researchers are developing an alternative medical treatment for this condition that may be more effective in a single dose because of its ability to resist deactivation by the plasminogen activator inhibitor, PAI-1, which reduces the effectiveness of the currently used medication.
Scientific Synopsis
Pleural loculation is a serious, common complication that can arise in both pediatric and adult patients with parapneumonic effusions. The current standard of care can involve surgery, which is associated with significant morbidity, or the use of low-molecular-weight urokinase (Abbokinase) or tissue plasminogen activator (tPA; Genentech) that is given through a chest tube or intrapleurally in multiple doses. A recent study demonstrated that the use of Abbokinase (no longer marketed or commercially available) for treating loculations associated with pleural effusions in pediatric patients was equivalent to surgery in terms of efficacy but entailed significantly less morbidity. We recently demonstrated that the zymogen form of high-molecular-weight urokinase (single-chain urokinase; scuPA) is superior to Abbokinase in resolving pleural loculations in a model of tetracycline-induced pleural effusion. In this study, scuPA was given as a single intrapleural dose and although not statistically significant, also exhibited a trend of being superior to tPA. Pleural loculations are characterized by increased fibrin deposition due to high levels of the endogenous plasminogen activator inhibitor, PAI-1, which would immediately inactivate enzymatically active lysins such as tPA and Abbokinase.
We hypothesize that scuPA, which is in its zymogen form and therefore not immediately inactivated by PAI-1, can reach the fibrin and be activated locally, leading to its superior activity in our studies and providing a basis for a single dose’s (in contrast to Abbokinase, for example, which is given multiple times) being sufficient to resolve pleural loculations. Our affirmative studies provide a strong rationale for the development of this potentially superior fibrinolysin for intrapleural use. Our objective is to secure program support to assist us in getting this drug to the clinic.
Lead Collaborators
University of Texas Health Science Center at Tyler
Steven Idell, M.D.
Scott & White Clinic, Central Texas
Arthur Frankel, M.D.
Attenuon, LLC, San Diego
Andrew Mazar, Ph.D.
Public Health Impact
A more effective pharmacotherapeutic approach to treating pleuritis would represent a significant advantage over the current standard of care, which is surgery or repetitive administration of active fibrinolysins subject to rapid inactivation, in terms of reducing cost and morbidity.
Outcomes
Work on this project is complete.
Project Details
- Pharmacokinetic/absorption, distribution, metabolism, and excretion (PK/ADME) studies
- Investigational New Drug (IND)-directed toxicology