Transcript Slide 1
Preserving Anti-Platelet Activity of Aspirin by Preventing Hydrolysis John C. Somberg*, Vasant V. Ranade*, Imran Qadeer*, Jackie Coleman**, Janos Molnar*** Rush University, Chicago, IL* Accumetrics, San Diego, CA** Academic Pharmaceuticals, Lake Bluff, IL*** Purpose of the Study Hydrolysis of aspirin markedly reduces the anti-platelet activity of aspirin (ASA) preventing the development of an effective IV formulation. This study evaluates a new IV formulation that prevents hydrolysis and preserves platelet inhibition. Benefits of ASA ISIS-2: Second International Study of Infarct Survival Reduction in odds of vascular death in days 0–35, by time from pain onset Time of randomization (hours from pain onset) SK better Placebo better Aspirin better Placebo better 0–1 2 3 4 Subtotal for 0–4 5–12 13–24 Subtotal for 5–24 Total for 0–24 0.5 * Size of squares indicates how much information available; lines and diamonds indicate 95% CIs SK; Streptokinase 1.0 1.5 0.5 1.0 1.5 Odds ratio and 95%CI* The ISIS-2 collaborative group. Lancet 1988; ii: 349–60. Benefits of ASA Kong et al, AJC 90:622, 2002 Feldman and Cryer, AJC 84: 404, 1999 Kotake et al. JCPT 31:237, 2006 Methods • Hydrolysis was determined by HPLC using a Luna column (5µ, 100x46 mm), a constant flow pump (Thermo-Finnigan Spectra System P2000) and a Spectra 200 programmable UV wavelength detector. • Platelet function was evaluated ex vivo using the “Verify Now” assay developed by Accumetrics that employs a method that is based upon the principle that agonist (arachidonic acid) -induced activated platelets bind to fibrinogen-coated polystyrene beads that agglutinate in whole-blood. Infrared-light transmittance through the chamber increases as the agglutinated platelets and beads fall out of the solution. Rate of Hydrolysis Percent not hydrolyzed Fresh 1 Day 40°C 1 month 40°C 6 months 40 °C New formulation ASA 99.8 99 99 99 Aqueous ASA 97.9 70 56 11 The Effect of ASA Solutions on Platelet Inhibition Percent Inhibition Platelets Fresh 1 month 6 months Aqueous ASA 26 0 0 New ASA Formulation 37 37 39 0 0 0 Vehicle Solution Conclusions Aqueous solutions of ASA hydrolyzes and this correlates with a diminished ex vivo ASA effect on platelet function A new formulation of ASA for IV administration shows no hydrolysis at 1 & 6 months of storage at 40°C This lack of hydrolysis of the new formulation correlates with ex vivo measured platelet inhibition by ASA Availability of an IV formulation of ASA may be useful in the treatment of acute coronary syndromes