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These data underline the important role of the proteolytic activity of Der p 1 in driving the allergic response in the lungs.

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The purpose of this work was to examine the biodistribution of poly( N5-hydroxyethyl-L-glutamine- co-L-glutamic acid) [poly(HEG- co-GA)] after intravenous administration to rats. Poly(γ-methyl-L-glutamate- co-γ-benzyl-L- glutamate) was prepared by ring-opening polymerization of the amino acid N-carboxyanhydride (NCA) derivatives. Sequential removal of the copolymer benzyl groups followed by reaction of the methyl ester groups with 2-amino ethanol gave poly(HEG- co-GA). Three samples of poly(HEG-co-GA) were pre pared with nominal HEG:GA compositions of 50:50, 95:5 and 90:10 mole %, and with weight average molecular weights ( Mw) of 37,000, 50,000 and 110,000 respectively. Following reaction with N-2[4-hydroxyphenyl]ethylamine (tyra mine), the copolymers were radioiodinated with 125 I and administered intra venously to male Wistar rats. 125 I-copolymer tissue distribution was assessed after 10, 15, 30 and 120 min and 8 h. It was found that the copolymer was removed rapidly from the blood compartment and excreted from the body via the kidneys. Only very low amounts of radioactivity were found in the liver and in other organs of the mononuclear phagocyte system. Degradation of the co polymer in vitro, as assessed by size exclusion chromatography (SEC), in plasma and urine over the time scale of the biodistribution experiment ap peared to be minimal.

Significant bioavailabilities of CGP 64128A were achieved following subcutaneous, intra-peritoneal and intra-tracheal administration. Pulmonary delivery represents a promising mode of non-parenteral dosing for antisense oligonucleotides. The dose-dependent increase in pulmonary bioavailability suggests that low doses may be retained in the lungs for local effects whereas higher doses may be suitable for the treatment of a broader spectrum of systemic diseases.