ABSTRACT
PURPOSE: To evaluate the pharmacokinetics and safety of aspirin delivered by a single, noninvasive, transscleral, coulomb-controlled iontophoresis (CCI) treatment; topical application; or by one intravenous (IV) injection. METHODS: Forty-one adult New Zealand White rabbits received either a single IV injection, topical, or CCI administration of aspirin at a concentration of 10 mg/mL. Histologic evaluation was performed in four CCI-treated eyes to assess safety. Pharmacokinetic distribution in all ocular tissues and fluids was studied at 0.5, 1, 2, 4, 6, and 8 hours after the treatments. Immediately after death, the eyes were dissected and salicylic acid (SA) concentration was determined by HPLC analysis. Blood was sampled at 0.5, 1, 2, 4, 6, and 8 hours, and plasma SA levels for systemic distribution were measured by HPLC analysis. RESULTS: No tissue damage was observed clinically or histologically. SA was found in all tissues and fluids throughout the study period of 8 hours. The highest concentrations of SA were observed with CCI immediately after treatment for all tissues and were the highest SA tissue peaks obtained by the studied delivery methods. IV administration demonstrated a delayed tissue peak of salicylate at 2 hours after administration. At 8 hours, ocular SA concentrations were in the same range for CCI and IV administration. IV injection resulted in blood plasma levels up to 28 times higher than CCI and remained significantly elevated until 8 hours after the treatments. CONCLUSIONS: CCI is a safe and effective method of administering aspirin to the eye while avoiding the systemic side effects associated with IV injection.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Aspirin/pharmacokinetics , Eye/metabolism , Administration, Topical , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Aspirin/administration & dosage , Aspirin/adverse effects , Drug Delivery Systems/instrumentation , Equipment Design , Injections, Intravenous , Iontophoresis/methods , Rabbits , Safety , Tissue DistributionABSTRACT
The effects of six polycations were studied in vitro on red blood cells (RBC) and in vivo after intravenous administration. Hemagglutination and hemolysis depended not only on the molar mass and the concentration of these polycations, but also on their chemical nature. The hemagglutination and hemolysis induced by poly(L-lysine), diethylaminoethyldextran, poly(dimethyldiallylammonium) chloride and poly[2-(dimethylamino)ethyl methacrylate] was low to moderate, whereas a severe hemolysis was induced by a partially quaternized poly[thio-1-(N,N-diethyl-aminoethyl)ethylene]. In the case of poly(epsilon-lysine), no significant hemagglutination nor hemolysis was observed. The presence of plasma proteins reduced both agglutination and hemolysis. This protective effect was enhanced when the polycations interacted with plasma proteins before contact with RBC. In the presence of albumin, the behavior depended on the polycation and on the order of addition of the three components of the suspension, namely albumin, polycation and RBC. Depending on the polycation, albumin-polycation complexes were either less active or more active on RBC than the same polycation in protein-free medium. In vivo the studied polycations induced an immediate mortality except poly(epsilon-lysine), which induced a delayed mortality. The minimal dose of polycations inducing immediate mortality paralleled their effect on RBC.
