Screening New Drugs for Urogenital Disease

Researchers at Roche Bioscience in Palo Alto, California (Hai Ming Tang and Gary Westbrock, under the guidance of Dr. David Blue) have developed a conscious telemetry-instrumented pig model to study potential pharmacological agents for the treatment of urogenital diseases. The use of implantable telemetry has allowed measurements of bladder and blood pressure to be obtained simultaneously in free-roaming pigs automatically for extended periods of time without the worry of tangled access cords or uncomfortable restraints.

Prior to the development of this assay, lower urinary tract activity was studied in an anaesthetized pig model. Although useful, the utility of this model was limited by the side effects of the anesthetic agent. Compensatory reflexes that attempt to lower heart rate in response to an increase in blood pressure are typically inhibited by anesthesia. In the conscious animals model these reflexes remain intact, resulting in animal data that are more predictive of what will happen when the drug is administered to human beings in clinical trials. The application of telemetry has not eliminated the use of the anesthetized model, but has provided additional information regarding the in vivo pharmacology of novel compounds that allow a more in-depth assessment of pharmacodynamics and activity of the test substance.

Previous success with the Data Sciences Intl PA-D70 single-channel pressure probes in dogs led the Roche team to choose the DSI D70-PCP implant in further telemetry research. This device provided the capability of simultaneous monitoring of bladder pressure, blood pressure, and ECG. Although they used the device to monitor bladder pressure and blood pressure simultaneously, they elected not to use the ECG channel since it was of no value in their studies. Transmitters were implanted by Dr. Michael Larson, a veterinarian at Roche Bioscience, under aseptic conditions and isoflurane anesthesia. The body of the implant was secured to the muscle of the lateral body wall with silk sutures. The catheter for BP measurement was inserted into the deep circumflex ileac artery and was advanced about 18 cm upstream into the aorta for the measurement of arterial blood pressure. The deep circumflex ileac artery was then ligated. The second catheter was introduced into the cranial aspect of the bladder. The catheter was inserted through a 3-4 mm long incision and stabilized with a pursestring suture around a plastic anchor located at the end of the catheter. This helped to keep the angle of approach to the bladder constant. The placement was toward the apex of the bladder as opposed to the bladder neck. This location was chosen in part because it was thought to have the least effect on the natural filling action of the bladder. A vascular access port (Sims Deltec, St. Paul, MN) was also implanted for intravenous administration of compounds via the jugular vein.

The pigs were monitored using waveform acquisition of the Dataquest LabPro software. Although collecting waveforms is extremely memory-intensive for the PC (1 MByte of data is collected every 10 minutes), it provided an accurate picture each time the pig voided. Running the Dataquest LabPro System on a 120 MHz Pentium PC eliminates any problems encountered with the large data files. To obtain real time hard copy on a polygraph, the telemetry signal was also simultaneously input to a DSI UA10 universal adapter. From the waveforms, it was possible to determine the time and duration of the void. Volume of the void was determined by urine collection.

This technique has been shown to be a very sensitive assay, as indicated by its ability to detect increases in abdominal pressure each time the pig grunts. For the lower urinary tract and cardiovascular system of conscious pigs, this model has proven useful for assessment of the pharmacological effects of novel compounds. According to the Roche Bioscience research team, the conscious animal model definitely provides information not available to us in the anesthetized animal model. It gives us a better idea of what the compound will do once it gets into human clinical trials.

Effect of Alpha1-Adrenoceptor (alpha1-AR) Antagonists in Dog Prostate/Blood Pressure Models Blue, D.R. Zhu, Q.-M. Isom, P. Young, S. Larson, M. Clarke, D. FASEB J 1996