Indobufen

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Abstract
Indobufen inhibits platelet aggregation by reversibly inhibiting the platelet cyclo-oxygenase enzyme thereby suppressing thromboxane synthesis. Clinical trials have evaluated the efficacy of oral indobufen in the secondary prevention of thromboembolic complications in patients with or without atrial fibrillation, in the prevention of graft occlusion after coronary artery bypass graft (CABG) surgery and in the treatment of intermittent claudication. In the secondary prevention of thromboembolic events indobufen 200mg once or twice daily was significantly more effective than no treatment although not as effective as ticlopidine 250mg once or twice daily, during 1-year nonblind clinical trials. Compared with placebo, indobufen 100mg twice daily significantly reduced the risk of stroke in a small 28-month trial of patients at increased risk of systemic embolism (50% had atrial fibrillation). Furthermore, in patients with nonrheumatic atrial fibrillation and a recent cerebrovascular event enrolled in the 1-year Studio Italiano Fibrillazione Atriale (SIFA) trial, indobufen 100 or 200mg twice daily was as effective as warfarin (titrated to produce an international normalised ratio of 2.0 to 3.5) in the secondary prevention of thromboembolic events; the incidences of the composite end-point of major vascular events (10.6 vs 9.0%) and recurrent stroke (5 vs 4%) were similar between treatments. In 2 large 12-month trials, the Studio Indobufene nel Bypass Aortocoronarico (SINBA) and the UK study, indobufen 200mg twice daily was as effective as aspirin (acetylsalicylic acid) 300 or 325mg plus dipyridamole 75mg 3 times daily in the prevention of early and late occlusion of saphenous grafts in patients after CABG surgery. Indobufen 200mg twice daily for 6 months significantly improved walking capacity compared with placebo, and caused a more pronounced improvement in both pain-free and total walking distance than either pentoxifylline 300mg or aspirin 500mg twice daily in separate 6- and 12-month studies of patients with intermittent claudication. Oral indobufen up to 200mg twice daily was generally well tolerated in >5000 patients with atherosclerotic disease. Adverse events (predominantly gastrointestinal), reported by 3.9% of patients, rarely required withdrawal from treatment. In the SINBA and UK studies, fewer adverse events and less gastrointestinal bleeding were seen with indobufen than with aspirin plus dipyridamole treatment, while in the SIFA trial, noncerebral bleeding events occurred significantly less frequently in indobufen than warfarin recipients (0.6 vs 5.1%) and major bleeding events occurred only in the warfarin group. Conclusion: Indobufen is as effective as warfarin in the prophylaxis of thromboembolic events in at risk patients with nonrheumatic atrial fibrillation, as aspirin plus dipyridamole in the prevention of CABG occlusion and may be more effective than aspirin or pentoxifylline in improving walking capacity in patients with intermittent claudication. The improved tolerability profile of indobufen (favourable gastric tolerance and reduced haemorrhagic complications) compared with aspirin 300 to 325mg 3 times daily or warfarin, in addition to a similar antiplatelet effect, suggests indobufen can be considered a drug with a definite role in the management of atherothrombotic events. In particular, indobufen may be an effective alternative for at risk patients with nonrheumatic atrial fibrillation in whom anticoagulant therapy is contraindicated or who are at higher risk of bleeding. Indobufen, an isoindolinyl phenyl-butyric acid derivative, reversibly inhibits platelet aggregation in vitro and ex vivo at the level of platelet cyclo-oxygenase, thereby suppressing thromboxane A2 production (a potent platelet activator). Ex vivo suppression of platelet thromboxane synthesis is evident within 2 hours of indobufen administration (98%), is still significant at 12 hours (89%) yet attenuated at 24 hours (47%), indicating reversible inhibition. Indobufen inhibits the release reaction and the secondary wave of aggregation induced by the platelet agonists adenosine diphosphate, adrenaline (epinephrine) and platelet activating factor in platelets taken from healthy volunteers and patients with ischaemic heart disease, atherosclerosis or angina pectoris. The maximum inhibitory effect on agonist-induced platelet aggregation was observed 2 hours after a single oral dose of indobufen 200mg and this inhibition was reversible, with platelet aggregation returning to baseline values within 24 hours. Indobufen alone or in combination with pentoxifylline reduces levels of β-thromboglobulin and platelet factor 4, markers of platelet activation. Other effects of indobufen include decreased platelet adhesiveness and an improvement in red blood cell deformability. Bleeding time is prolonged following indobufen administration, although within the upper limit of normal and for a shorter time than with aspirin (acetylsalicylic acid) or ticlopidine. Improvements in microcirculatory parameters including skin blood flow and the venoarteriolar reflex were shown in patients with intermittent claudication following indobufen therapy. Indobufen inhibited thrombus formation in animals and prevented graft occlusion following vascular surgery. Indobufen is rapidly and completely absorbed after oral administration, reaching peak plasma concentrations within 2 hours. The elimination half-life (t1/2β) is about 7 hours and the low apparent volume of distribution of 15L is a reflection of the high plasma protein binding (>99%) of the drug. The fraction of the administered dose excreted in urine within 48 hours of administration is about 70 to 80%, with most excreted via the kidney as glucuronic acid conjugates and 11 to 13% excreted as unchanged drug. Excretion rates are not affected by route of administration (oral or intravenous) and renal clearance is...