Osteoarthritis (OA) is a degenerative joint disease that has no FDA-approved treatment. The current standard of care does not address the regeneration of the damaged cartilage. Human growth hormone (hGH) is part of the insulin-like growth factor (IGF)-1 axis. There has been preclinical data that suggest its potential regenerative property in the joint. However, unformulated recombinant hGH (rhGH) is short-lived in the joint, and does not provide a desirable pharmacokinetic (PK) profile to support a clinical treatment paradigm. Polyethylene glycol (PEG)ylation is a potential method to extend the half-life of rhGH in the joint. The purpose of this study was to delineate the PK/PD profile of PEG-rhGH in the knee joint in a rat preclinical model of OA. After intra-articular (IA) injection of 100 μg into a rat knee joint that underwent medial meniscectomy, PEG-rhGH exhibits 2-fold longer half-lives in joint than native hGH. However, PEG-rhGH has a much longer systemic exposure. IA injections of PEG-rhGH also resulted in higher levels of IGF-1 in the joint and serum when compared with native rhGH. In order to develop PEG-rhGH as an IA therapeutic treatment for OA, careful dose selection is necessary to avoid systemic effects while retaining its anabolic efficacy in the joint.

There is a decrease in glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) and an increase in mean arterial pressure (MAP) and renal vascular resistance (RVR) after release of bilateral ureteral obstruction (BUO) of 24 hours duration. The present studies examine the role of endothelium-derived relaxing factor (EDRF) in the renal hemodynamics of sham-operated rats (SOR) and rats in which BUO of 24 hours duration was unilaterally released. In both groups of rats, renal function and blood pressure were measured in the awake state under basal conditions and after administration of L-arginine (L-arg), the substrate for EDRF synthesis, followed by NwNAME, an L-arg antagonist, or after administration of NwNAME followed by L-arg. Administration of L-arg alone to SOR did not affect renal function, MAP or RVR. In SOR given L-arg and then NwNAME, there was significantly decreased GFR and ERPF and increased MAP and RVR. When NwNAME was given initially, similar changes were obtained, and these were reversed by the administration of L-arg. Rats given L-arginine immediately after unilateral release of BUO of 24 hours duration had significantly greater GFR and ERPF values and lower MAP and RVR than temporal controls. NwNAME given to BUO rats decreased renal function further and increased MAP and RVR. We found a dose-dependent increase in GFR and ERPF and a dose-dependent decrease in MAP and RVR in both SOR and rats with BUO given increasing amounts of L-arg. There was also a dose-dependent decrease in GFR and ERPF and an increase in MAP and RVR in SOR and rats with BUO given increasing amounts of NwNAME or NGNMA, the two different antagonists of L-arg. In another set of experiments, SOR and rats with BUO were given L-arg preoperatively (that is, 24 hr prior to study). Both groups of rats had significantly higher GFR and ERPF values and lower MAP and RVR than control rats. Sham-operated rats given NwNAME 24 hours prior to study had significantly lower GFR and ERPF and higher MAP and RVR than untreated rats. Rats with BUO given NwNAME prior to obstruction had no measurable renal function and had significantly higher values for MAP after release of obstruction. These studies confirm the role of L-arg administration, and presumably EDRF, in the regulation of MAP and renal function in sham-operated rats. The results of this study also suggest decreased availability of arginine for EDRF synthesis in rats with BUO.(ABSTRACT TRUNCATED AT 400 WORDS)