Indobufen

Publisher Website
Google Scholar
Abstract
Indobufen is an inhibitor of platelet aggregation which acts by reversibly inhibiting the platelet cyclo-oxygenase enzyme. Improvements in walking distances and microcirculatory parameters have been achieved during therapy with indobufen in patients with peripheral vascular disease and intermittent claudication. Indobufen has been shown to be as effective as aspirin plus dipyridamole in preventing the reocclusion of coronary and femoro-popliteal artery bypass grafts and has been shown to significantly reduce platelet deposition on haemodialysis membranes. Initial studies have also indicated that indobufen may have a prophylactic effect on the incidence of secondary thrombotic events following transient ischaemic attack or mild stroke and may be effective in the prophylaxis of migraine. Indobufen is well tolerated following oral administration and has been associated with a low incidence of adverse effects rarely requiring withdrawal of treatment. Thus, available evidence indicates that indobufen may be an effective alternative to aspirin for the treatment of cerebral, peripheral and coronary vascular diseases with the advantage of a lower incidence of gastrointestinal effects compared to high dose aspirin, rendering indobufen more suitable for longer term therapy. Indobufen is an isoindolinyl phenyl-butyric acid derivative that produces reversible inhibition of platelet aggregation in vitro and ex vivo. Platelet cyclo-oxygenase is reversibly inhibited by indobufen and this results in decreased production of thromboxane B2, a potent activator of platelet aggregation. The drug inhibits the second wave of aggregation induced by adenosine diphosphate (ADP), epinephrine (adrenaline) and platelet activating factor (PAF) in platelets from healthy volunteers and from patients with occlusive vascular disease, and has a dose-dependent inhibitory effect on collagen- and arachidonic acid-induced aggregation. A maximal inhibitory effect on agonist-induced platelet aggregation is observed 2 hours after a single oral dose of indobufen 200mg. This inhibition is still significant (90%) after 12 hours and is reversible within 24 hours. Indobufen therapy (200mg twice daily) significantly inhibits spontaneous platelet aggregation ex vivo compared with placebo in platelets from atherosclerotic patients, and this is evident 2 to 8 hours after administration. Other effects include a reduction in the platelet levels of adenosine triphosphate (ATP), serotonin (5-hydroxytryptamine), platelet factor 3 (PF3), PF4 and β-thromboglobulin (BTG), decreased platelet adhesiveness in platelets from healthy volunteers and from atherosclerotic patients and an improvement in red blood cell deformability in patients with occlusive vascular disease. Bleeding time is prolonged following indobufen administration, with a maximal effect 2 hours after administration; however, this increase is not clinically relevant and values remain within the upper normal limit at all times. Improvements in microcirculatory parameters, including resting and standing skin blood flow and the venoarteriolar reflex have been found in patients with intermittent claudication and diabetes following indobufen therapy. Indobufen demonstrated antithrombotic activity in vivo in animals against the lethal thrombotic effects of epinephrine and collagen and prevented graft occlusion following vascular surgery. Indobufen is readily absorbed following oral administration with peak plasma concentrations of 12.5 to 14.9 mg/L being attained at 2 hours after a single dose of 100mg. Steady-state peak plasma concentrations of 16.7 and 29.2 mg/L are achieved after oral administration of indobufen 100 and 200mg twice daily for 7.5 and 5 days, respectively. Indobufen is highly bound to plasma proteins (> 99%) and this is reflected in its low apparent volume of distribution (13 to 15L). The elimination half-life of indobufen is within the range of 6 to 8 hours in healthy volunteers and about 75% of the dose is recovered in urine within 48 hours of administration. About 13% of the dose is excreted unchanged and the remainder as a glucuronic acid conjugate. In the elderly and in patients with renal insufficiency, the area under the plasma concentration-time curve and plasma elimination half-life of indobufen are significantly prolonged and dose reduction is required. Indobufen 200mg twice daily improves walking distances in patients with intermittent claudication. Walking distances were significantly improved in patients receiving indobufen compared with patients receiving placebo (p < 0.05) within 10 days of starting therapy, and continued to improve during 6 months of indobufen therapy. In one nonrandomised comparative study, indobufen 200mg twice daily was found to cause a more marked improvement in pain-free walking distance and total walking distance than aspirin 500mg twice daily after 1 year. Several studies evaluated the efficacy of indobufen in improving graft patency following surgery. Indobufen 200mg twice daily was as effective as aspirin 975mg + dipyridamole 225mg daily in reducing the incidence of coronary artery bypass graft (CABG) reocclusion, which occurred with a frequency of 34% in both treatment groups after 1 year of therapy. Platelet accumulation and lesion formation following carotid endarterectomy were reduced in patients receiving indobufen 200mg twice daily compared with placebo after a 6-month treatment period. Preliminary investigation of the use of indobufen in the secondary prevention of occlusive vascular events has indicated a potential prophylactic benefit of indobufen in patients following transient ischaemic attack, mild stroke or acute myocardial infarction. In one study the incidence of secondary cardiovascular events in patients treated with indobufen 100mg twice daily was 5% compared to 15% in the placebo group after 26 months. An initial study has indicated that indobufen may also have a prophylactic effect in patients with classic or common migraine. Clinical trials evaluating the efficacy of indobufen in reducing platelet aggregation on haemo-dialysis membranes have found a significant reduction in membrane occlusion after administration of indobufen 200mg twice daily for 7 days (30%) compared to placebo (51.5%) suggesting that indobufen therapy improves the efficiency of haemodialysis. Indobufen 200mg twice daily has been well tolerated in patients with vascular disease, with adverse effects occurring in approximately 3 to 9% of patients; discontinuation of therapy has rarely been necessary (in approximately 1% of those treated). The majority of adverse effects reported during treatment are gastrointestinal and include dyspepsia, abdominal pain, constipation, nausea and vomiting. Haemostasis and coagulation disorders and skin and central nervous system (CNS) disorders have been reported in a small number of patients. In comparative studies, the incidence of adverse effects was lower in patients receiving indobufen 200mg twice daily (9%) compared with aspirin 975mg daily plus dipyridamole 225mg daily (18%). The oral daily dose of indobufen is generally 200 to 400mg, given in 2 divided doses after meals. Dosage reductions are necessary in the elderly and in patients with renal insufficiency.

This publication has 0 references indexed in Scilit: