In vitro model to test the thrombogenicity of coronary stents.

Thrombotic occlusion is a major complication limiting the application of stents in coronary arteries. In an in vitro model we investigated the thrombogenicity of different stent materials and several medical regimens to prevent thrombotic occlusion. Experiments were conducted in a closed system of silicon tubing with circulating citrated platelet rich plasma of healthy volunteers (n = 7) and of patients (n = 7 for each condition). Patients were either treated with phenprocoumon or with high or low dose heparin in combination with aspirin alone (100 mg) or aspirin (990 mg) plus dipyridamole (225 mg). After placement of tantalum wire stents into the system platelet aggregates were visible after 13.5 +/- 3.0 min, and occlusion occurred after 15.0 +/- 3.5 min. Similarly, with implanted stainless steel stents aggregation was seen after 13.0 +/- 3.5 min and thrombosis occurred after 14.5 +/- 3.5 min (p < 0.001 vs control without stent). Microscopic examination revealed combined platelet fibrin thrombi occluding the lumen. Platelet components predominately covered stent wires, particularly at crossing points. In all experiments high-dose heparin prevented platelet aggregate formation and stent occlusion independently of additional aspirin or aspirin plus dipyridamole; perfusion time > 60 min (p < 0.001 vs no heparin). Low-dose heparin could not prevent clotting. With aspirin alone aggregates were visible after 16.0 +/- 4.0 min and clotting occurred after 23.0 +/- 5.0 min. In combination with dipyridamole aggregates were visible after 15.5 +/- 5.0 min and clotting after 21.0 +/- 4.0 min (NS vs aspirin alone). Phenprocoumon prevented platelet aggregate formation and stent occlusion; perfusion time > 60 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Preparation and in vitro-in vivo evaluation of none gastric resident dipyridamole (DIP) sustained-release pellets with enhanced bioavailability.

The objective of this study was to develop none gastric resident sustained-release pellets loaded with dipyridamole with a high bioavailability. Two different kinds of core pellets, one containing citric acid as a pH-modifier (CAP) and, the other without pH-modifier (NCAP) were prepared by extrusion-spheronization and then coated with mixtures of enteric soluble and insoluble polymers (referred to as CAP(1) and NCAP(1)) or insoluble polymer alone (referred to as CAP(2) and NCAP(2)). The relative bioavailability of the sustained-release pellets was studied in fasted beagle dogs after oral administration using a commercially available immediate release tablet (IRT) as a reference. The in vitro release, in vivo absorption and in vitro-in vivo correlation were also evaluated. Results revealed that the plasma drug concentrations after administration of CAP(2), NCAP(1) and NCAP(2) were undetectable, indicating that the drug release was almost zero from the preparations throughout the gastro-intestinal tract. The C(max), T(max) and AUC((0→24)) of CAP(1) were 0.78 ± 0.23 (µg/ml), 3.80 ± 0.30 (h), and 6.74 ± 0.47 (µg/mlh), respectively. While the corresponding values were 2.23 ± 0.32 (µg/ml), 3.00 ± 0.44 (h) and 9.42 ± 0.69 (µg/mlh) for IRT. The relative bioavailability of CAP(1) was 71.55% compared with IRT. By combined incorporation of a pH-modifier into the core of pellets to modify the inner micro-environment and employing mixtures of enteric soluble and insoluble polymers as a retarding layer, drugs with high solubility in stomach and limited solubility in small intestine, such as DIP, could be successfully formulated as sustained release preparations with no pH-dependence in drug release and enhanced bioavailability.

Perioperative suppression of platelet adherence to small-diameter polytetrafluoroethylene (PTFE) grafts.

The perioperative effect of platelet antagonists on small-diameter polytetrafluoroethylene (PTFE) grafts was evaluated in forty-six New Zealand white male rabbits receiving either dipyridamole (DPM) 100 mg/kg/day (n = 10; group 1), aspirin (ASA) 10 mg/kg/day (n = 10; group 2), a combination of ASA 10 mg/kg/day and DPM 10 mg/kg/day (n = 9; group 3) or 100 mg/kg/day (n = 10; group 4), or placebo (n = 7) as single daily doses. All regimens began 72 hr prior to insertion of a 20 x 3-mm internal diameter PTFE interposition aortic graft. Autologous indium-111 labeled platelets were injected immediately after implantation. Graft and an equivalent segment of aorta were harvested after 48 hr. Graft platelet adherence index (GPAI) was calculated as the graft:reference aorta ratio of emissions. The GPAI in the control group was 238 +/- 46 (mean +/- SD). Single regimen antiplatelet agents in groups 1 and 2 reduced mean GPAI to 47 +/- 38 and 40 +/- 12, respectively. The combination regimen in group 3 lowered mean GPAI to 43 +/- 8 and in group 4 to 21 +/- 7. Platelet uptake in PTFE grafts at 48 hr is significantly lowered to 8.8 to 19.7% of control by perioperative antiplatelet agents given as a single daily oral dose (P less than 0.001). ASA alone and DPM alone provided similar suppression of platelet uptake, but combination ASA + low dose or high dose DPM gave significantly greater (P less than 0.001) suppression of early platelet deposition than the single agent regimens. These results support perioperative administration of combination oral antiplatelet agents as adjunctive therapy in small diameter prosthetic graft implantation.