preserving anti-platelet activity of aspirin by preventing hydrolysis john c. somberg*, vasant v....
TRANSCRIPT
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 ASAISIS-2: Second International Study of Infarct Survival
Reduction in odds of vascular death in days 0–35, by time from pain onset
Odds ratio and 95%CI*
0–1 2 3 4 Subtotal for 0–4
5–12 13–24 Subtotal for 5–24
Total for 0–24
The ISIS-2 collaborative group. Lancet 1988; ii: 349–60.
* Size of squares indicates how muchinformation available; lines anddiamonds indicate 95% CIs
0.5 1.0 1.5 0.5 1.0 1.5
Time of randomization(hours from pain onset)
SKbetter
Placebobetter
Aspirinbetter
Placebobetter
SK; Streptokinase
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 1 month 6 months 40°C 40°C 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
Vehicle Solution 0 0 0
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