Search

BACKGROUND Prostate specific antigen (PSA) is a kallikrein family member with serine protease activity commonly used as a diagnostic marker for prostate cancer. We recently described anti-angiogenic properties of PSA [Fortier et al.: JNCI 91:1635–1640]. METHODS Two forms of PSA were cloned and expressed in Pichia pastoris: one, an intact PSA with an N-terminus of IVGGVS…; the second, an N-1 PSA variant. The recombinant proteins were tested for serine protease activity and for anti-angiogenic activity in vitro and in vivo. RESULTS The rate of substrate hydrolysis by the intact recombinant PSA was similar to that of PSA isolated and purified from human seminal plasma. In contrast, the N-1 PSA variant lacked serine protease activity. In an endothelial cell migration assay, the concentration that resulted in 50% inhibition (IC50) was: 0.5 μM for native PSA, 0.5 μM for intact recombinant protein, and 0.1 μM for the N-1 variant PSA. Both the intact recombinant and the N-1 recombinant PSA inhibited angiogenesis in vivo. CONCLUSIONS Purified recombinant PSA inhibits angiogenesis, proving the concept that PSA is an anti-angiogenic, and serine protease activity, as determined by synthetic substrate hydrolysis, is distinct from the anti-angiogenic properties of PSA. Prostate 56: 212–219, 2003. © 2003 Wiley-Liss, Inc.

Introduction MoxDuo™ is a novel dual opioid combination of morphine and oxycodone in a 3:2 ratio that has been shown in animal models and clinical studies to have advantages of improved opioid related adverse events vs single entity opioids including decreased somnolence, dizziness, nausea and vomiting. Methods 6 groups of approximately 30 subjects undergoing excision of hammertoe under local anesthesia were randomized once pain levels reached at least 4 (avg 6.6), 0–10 NPRS scale to MoxDuo™ 12 mg morphine/8 mg oxycodone (12/8), MoxDuo™ 6 mg morphine/4 mg oxycodone (6/4), Morphine sulphate 12 mg (MS 12), Oxycodone hydrochloride 8 mg (Oxy 8), MS 6, and Oxy 4. The primary efficacy measure was SPID-24(Sum of Pain Intensity Differences 0 to 24 hrs post surgery) An oxy to mor conversion ratio of 1 to 1.5 was used for morphine equivalent dose (MED) comparisons. Results The three MED groups, MoxDuo™ 6/4, MS 12, and Oxy 8 had highly comparable analgesic effects as measured by SPID, TOTPAR, and other pain assessment endpoints. Study dropouts and incidence of many common opioid adverse events (nausea, emesis, dizziness) was significantly lower in MoxDuo™ group compared to the MED of MS or Oxy. In non-MED comparisons, MoxDuo™ 12/8 and 6/4 were shown to be superior to each of their component doses. Discussion These results, data of MoxDuo™ vs Percocet (oxycodone-paracetamol) after total knee replacement and preliminary data from studies underway with Prof. Dr. Neugebauer using IV combination vs. IV morphine following hip replacement will be discussed.

The pharmacological administration of endorphins as well as the specific opiate antagonist naloxone have been utilized to study the possible physiological and behavioral roles for endogenous opiates. While the most universally accepted function for endorphins involves their attenuation of the perception of painful stimuli, other important physiological roles for these substances have recently been suggested. Our research efforts have been focused upon the potential role of endorphins in heat adaptation and in shock states as well as in their effects on pituitary function and in electroconvulsive shock. These investigations are the primary focus of this review which also briefly examines the possible involvement of endorphins in such diverse functions as grooming behavior, memory, seizures, and sexual behavior.