Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Pilot Study Investigating the Pressor Activity of Vasopressin Infused by the Subcutaneously Implanted SMP 200 Microinfusion Pump in the Telemetered Rat Christophe Bory C, Philippe Legé, Estelle Chalencon, Jean-Paul Briffaux, Stéphane Milano WIL Research Europe-Lyon, France l MATERIAL AND METHODS, continuedl RESULTSl RESULTS, continuedl INTRODUCTION Implantable lab animal infusion pumps have become a very convenient and cost effective method to deliver drugs. When used in combination with telemetry, implantable infusion pumps allow a more sensitive and powerful means of detecting drug induced therapeutic and/or adverse effects than when drugs are delivered in restrained conditions or by tethered infusion. The 2nd generation iPRECIO® SMP-200 (Primetech, Japan) is an implantable, transcutaneously-refillable and programmable pump for small lab animals, based on a mini-peristalsis flow infusion mechanism. l OBJECTIVES The aim of that study was to assess the accuracy of SMP-200 pump in telemetered rat by using the effects of infused vasopressin on blood pressure as an endpoint. l MATERIAL AND METHODS Vasopressin (arginine vasopressin, AVP; antidiuretic hormone, ADH) is a peptide hormone formed in the hypothalamus, then transported via axons to, and released Figure 1: Key features of the SMP-200 pump and catheter assembly from, the posterior pituitary into the blood. SMP-200 pump was used in post-recovery (delayed) infusion mode, whereby saline is infused first to ensure patency of the catheter and the drug was infused AVP has two principal sites of action: kidney and blood vessels. The primary function subsequently. After saline infusion at 5 µL/h for one week, the remaining vehicle was of AVP in the body is to regulate extracellular fluid volume by affecting renal handling withdrawn from the pump reservoir and replaced by AVP dose A, infused for 24h at of water, although it is also a vasoconstrictor and pressor agent (hence, the name 30 µL/h. The pump was then was programmed for a 24h-stop (no infusion), at the “vasopressin”). AVP acts on renal collecting ducts via V2 receptors to increase water end of which the reservoir was washed out and refilled with AVP dose B, infused at permeability (cAMP‑dependent mechanism), which leads to decreased urine 30 µL/h for 24 hours. formation (hence, the antidiuretic action of “antidiuretic hormone”). This increases blood volume, cardiac output and arterial pressure. At the end of the surgical recovery period, the average actual volume of saline infused was in accordance with the pre‑programmed nominal volume (840 µL ± 5%). AVP at 200 ng/h produced a significant increase in blood pressure (+20 mmHg diastolic) which started at the onset of infusion and was maintained for 24 hours, as expected. Of note, in 3 out of 6 animals, a higher deviation (± 10%) from the nominal pre-programmed targeted volume was noted. Despite that discrepancy, the overall precision of volume delivering was considered as very satisfactory. A secondary function of AVP is vasoconstriction. AVP binds to V1 receptors on vascular smooth muscle to cause vasoconstriction through the IP3 signal transduction pathway and Rho-kinase pathway, which increases arterial pressure; however, the normal physiological concentrations of AVP are below its vasoactive range. Normal plasma AVP concentrations are <4 pg ml-1. AVP has a half-life of 10–35 min, being metabolized by vasopressinases which are found in the liver and kidney. Because of its vasoactive potency and its short half-life, AVP was considered as an ideal drug candidate for testing the infusion capabilities of the SMP-200 pump, analyzed through the effects on blood pressure. l CONCLUSIONS The SMP-200 infusion pump is implantable, programmable and refillable and has the benefit of providing sophisticated infusion protocols in tetherless, free moving animal. In combination with this gold standard of telemetry, SMP-200 infusion pump is leading to ever more sensitive and powerful means of detecting drug induced therapeutic and/or adverse effects. The precision of SMP-200 was tested in 6 rats telemetered for blood pressure and infused with two different dose levels of AVP (dose A: 20 ng/h; dose B: 200 ng/h). A week before pump implantation, rats were instrumented with a TL11M2-C50‑PXT implant (DSI), placed in the peritoneal cavity and the pressure catheter inserted into the abdominal aorta. Then, the infusion catheter of SMP-200 was implanted into the femoral vein and the pump inserted under the skin of the right flank. The original SMP-200 catheter was cut 2 cm after the exit port of the pump and replaced by a rat femoral tapered PU 3 French catheter with rounded tip (SAI, USA). The end of the SMP-200 tube was connected to the PU catheter via a 22 gauge coupler. SOT 55 Annual Meeting th Figure 2: Schematic representation of the infusion protocol Telemetered blood pressure (systolic, mean and diastolic) signal was acquired (500 Hz) and analyzed with Notocord hem 4.2 (Notocord Systems, France). Blood pressure was averaged for 5 min every 30 min. Telemetry data are presented as means ± SEM, with n = 6. At the end of the 24h-infusion of AVP at 20 ng/h, the same level of precision was observed (720 µL ± 5%) but no significant vasopressor effect was detected. This pilot study demonstrated that, when implanted in vivo, the pump is accurately delivering the loaded drug. Vasopressin at 200 ng/h produced a significant increase in blood pressure (+20 mmHg diastolic) in the telemetered rat. The vasoactive effect started at the onset of the infusion and was sustained during the entire programmed duration of infusion. Nonetheless, in 3 out of the 6 animals instrumented, a slight (10%) higher deviation from the nominal preprogrammed targeted volume was noted. The precision of these preliminary results was very encouraging, and the reason for the discrepancy observed during the second vasopressin infusion session is under investigation with several causes being considered.