In-Vivo Evaluation of an In Situ Polymer Precipitation Delivery System for a Novel Natriuretic Peptide

Abstract

This study reports on the release of a novel natriuretic peptide, CD-NP, from an in situ polymer precipitation delivery system. Following extensive screening of in-vitro release profiles, an in-vivo evaluation of the efficacy of the delivery system was carried out in Wistar rats. Gel injection was performed subcutaneously on the back of the rats. A secondary messenger, cyclic Guanosine 3′5′ Monophosphate (cGMP), was tested for verification of CD-NP bioactivity, in addition to direct measurements of CD-NP levels in plasma and urine using a radio-immuno assay. Plasma evaluation showed an elevated level of CD-NP over 3 weeks' duration. Unexpectedly, plasma cGMP level followed a decreasing trend over the same duration despite high CD-NP level. Loss of drug bioactivity was ruled out as a high level of CD-NP and cGMP excretion was observed in the treatment group as compared to baseline readings. This unexpected low-plasma cGMP levels and high-urinary cGMP excretion suggest that there might be other compensatory responses to regulation of the CDNP bioactivity as a result of the high drug dosing. The results stress the importance of assessing the overall bioactivity of released drug (in-vivo) concurrently in addition to measuring its concentrations, to determine the correct release profile.

Chronic subcutaneous brain natriuretic peptide therapy in asymptomatic systolic heart failure

“…In the current proof of concept study, our main objective was to define the cardiorenal response and assess for tolerance to SQ BNP administration and intravascular volume expansion after 12 weeks of SQ BNP therapy in asymptomatic HF. The results have important implications, as loss of therapeutic actions as seen with other peptide therapies would render chronic exogenous BNP therapy ineffective in asymptomatic HF. We have previously reported in asymptomatic systolic HF that the natriuretic peptide system is implicated in an impaired diuretic/natriuretic response to volume expansion.…”

“…Intervention in early, asymptomatic stages of HF may ultimately reduce the burden of HF in the community. However, chronic administration of a peptide may result in tolerance and lack of beneficial actions . The current study was therefore designed to assess the cardiorenal response to intravascular volume expansion after 12 weeks of SQ BNP vs. placebo among subjects with asymptomatic systolic HF.…”

In vivo Evaluation of Cenderitide-Eluting Stent (CES) II

“…The plasma was stored in polystyrene tubes at −80°C for further analysis. Radio-immumo Assay (RIA) Kit obtained from Perkin Elmer Life Science was used to evaluate plasma CD-NP and cGMP concentrations 7, 22 . The RIA assay works on competition between 125 I-peptide and CD-NPs binding onto a limited quantity of antibodies.…”