Single oral dose study of two isosorbide-based aspirin prodrugs in the dog

Abstract

The objective of this study was to compare two aspirin prodrugs, isosorbide diaspirinate (ISDA) and a nitroaspirin (ISMNA), with aspirin in terms of effects on dog platelet function after administration of a single oral dose. Groups of six dogs were administered ISDA (2 mg kg -1 ), ISMNA (4 mg kg -1 ) or aspirin (2 mg kg -1 ). Blood was sampled at 1, 2, 4, 8, 12 and 24 h postdosing and evaluated for capacity to generate post-clotting thromboxane (TX)B 2 . The aggregation response to arachidonic acid (AA) (100 M), ADP (30 M) or collagen (10 g mL -1 ) was estimated at each time-point using the whole blood impedance method. Plasma ISMN following oral administration of ISMNA was also measured and compared with plasma ISMN following administration of a physical mixture of ISMN and aspirin. ISDA administration (2 mg kg -1 ) was associated with a significant reduction (P < 0.05) in serum TXB 2 at 12 and 24 h (>90%) post-dosing and persistent inhibition of AAinduced platelet aggregation. ISDA administration caused a more marked depression of post-clotting TXB 2 levels than aspirin in this study, although its ability to inhibit platelet aggregation was less consistent than that of aspirin. The nitroaspirin ISMNA was least effective at inhibiting platelet aggregation response or TXB 2 production. The ISMN AUC 0-24 h for the ISMNA-treated dogs was 77% of that for the physical mix-treated dogs and the t max was delayed. This study indicates that the two aspirin esters cause aspirin-like effects on platelet function, probably through aspirin release, when administered orally to dogs.

Serum thromboxane B2 (TXB2) Determination is Influenced by Sample Incubation Temperature in Healthy Beagle Dogs

“…As expected, the results of our study showed a significant difference in serum TXB 2 concentration between both groups of samples, 1098 ± 346 g/l (incubation at 37 C for one hour) versus 550 ± 257 g/l (incubation at room temperature) for one hour. Serum TXB 2 concentrations in both groups of samples showed marked intra-and inter-individual variations, which is in accordance with previously reported results (Gilmer et al 2003;Yamanaka et al 1993).…”

“…1. Serum thromboxane B 2 , in two groups of samples; one was incubated at 37 ºC for one hour, the second was incubated at room temperature for one hour is the most frequently used means of evaluating COX inhibitors mainly because this approach reduces variability due to sampling, which profoundly affects direct measurement of highly unstable TXA 2 (Blain et al 2002;Brideau et al 1996;Gilmer et al 2003;Lees et al 2004;Patrignani et al 1997;Van Hecken et al 2000). TXA 2 is normally converted to its stable product TXB 2 (Hamberg et al 1975).…”

“…Although validated methods for in vitro whole blood assays for COX-1 and COX-2 have already been published (Brideau et al 1996;Patrignani et al 1997) and used by several research groups (Blain et al 2002;Cryer and Feldman 1998;Gilmer et al 2003;Panara et al 1999;Sessions et al 2005;Van Hecken et al 2000), literature review on normal values of TXB 2 in canine serum and the measurement of serum TXB 2 revealed inconsistent data, especially on the preparation of serum samples and the methods of measurement used (RIA, ELISA). Therefore, we decided to investigate the influence of recommended sample incubation at 37 C for one hour on serum TXB 2 concentration compared to incubation at room temperature in healthy beagle dogs.…”

“…Serum TXB 2 is predominantly derived from platelets, with leukocytes being another source (Higgs et al 1983;Wallace and Ma 2001). In response to endogenous thrombin formation, i.e., clot formation, platelet COX-1 is maximally stimulated to produce TXA 2 , which is the major arachidonic acid metabolite produced by platelets, via COX-1, and one of the most potent platelet aggregating agent and vasoconstrictive substances known (Gilmer et al 2003;Kamath et al 2001;Smith 1989;Wallace and Ma 2001). Highly unstable TXA 2 (t 1/2 at 37 C is 32 ± 2 seconds) is converted into a stable hydrolysis product TXB 2 (Hamberg et al 1975).…”

“…The measurement of serum TXB 2 production by platelets following blood coagulation is a specific and most frequently used test for evaluation of platelet COX-1 activity in humans and other species (Brideau et al 1996;Blain et al 2002;Gilmer et al 2003;Jones et al 2002;Patrignani et al 1997;Rinder et al 2002;Sessions et al 2005;Van Kraaij et al 2002). Whole blood TXB 2 production is measured from clotted blood samples obtained from the patient after administration of NSAID or after collection of blood into tubes preloaded with NSAID.…”