DRUG EVALUATION

Drugs 44 (3): 445-464, 1992 0012-6667/92/0009-0445/$10.00/0 © Adis International Limited. All rights reserved.

DRE1118

Indobufen A review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Efficacy in Cerebral, Peripheral and Coronary Vascular Disease

Lynda R, Wiseman, Andrew Fitton and Micaela M, Buckley Adis International Limited, Auckland, New Zealand

Various sections of the manuscript reviewed by: R.C. Becker, Thrombosis Research Center, University of Mas­sachusetts Medical School, Worcester, Massachusetts, USA; G. Belcaro, Via Vespucci 65, 65100 Pescara, Italy; J.P. Boissel, Hopital Neuro-Cardiologique, Unite De Pharmacologie Clinique. Departement Methodologie et Es­sais Therapeutiques, Lyon, France; J. Caldwell, Department of Pharmacology and Toxicology, St Mary's Hospital Medical School, London, England; G. Davi, Instituto di Medicina Interna e Geriatria, Clinica Medica Generale, E Terapia Medica II, Palermo, Italy; G. de Gatano, Consorzio Mario Negri Sud, Centro di Richerche Famracol­ogiche e Biomediche, S. Maria Imbaro (Chieti), Italy; R. Hattori, Kyoto University Hospital, Kyoto. Japan; H. White, Cardiovascular Research. Green Lane/National Women's Hospital, Auckland, New Zealand,

Contents

446 448 448 448 449 451 452 452 453 453 453 454 454 455 455 455 457 457 458 459 459 460 460 460 461 461

Summary I. Pharmacodynamic Properties

1.1 Effects of Indobufen on Platelet Function 1.1.1 Platelet Thromboxane Synthesis 1.1.2 Platelet Aggregation 1.1.3 Platelet Release Reaction 1.1.4 Platelet Adhesion

1.2 Effects on Blood Coagulation and Erythrocyte Deformability 1.3 Effects on Microcirculatory Parameters 1.4 In Vivo Effects in Experimental Models of Thrombosis

2. Pharmacokinetic Properties 2.1 Absorption 2.2 Distribution and Elimination 2.3 Influence of Age and Renal Disease on Pharmacokinetics

3. Therapeutic Use 3.1 Treatment of Occlusive Vascular Disease 3.2 Prophylactic Use in Occlusive Vascular Disease

3.2.1 Arterial Bypass Graft Surgery, Carotid Endarterectomy and Coronary Angioplasty 3.2.2 Transient Ischaemic Attack and Stroke 3.2.3 Deep Vein Thrombosis 3.2.4 Haemodialysis 3.2.5 Migraine

4. Tolerability 5. Drug Interactions 6. Dosage and Administration 7. Place of Indobufen in Therapy

446

Summary Synopsis

Drugs 44 (3) 1992

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.

Pharmacodynamic Properties

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 J3-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 intermitt~nt 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.

Pharmacokinetic Properties

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 ofindobufen 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

Indobufen: A Review 447

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.

Therapeutic Use

Tolerability

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 < O.OS) 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 SOOmg twice daily after I year.

Several studies evaluated the efficacy of indobufen in improving graft patency following sur­gery. Indobufen 200mg twice daily was as effective as aspirin 97Smg + dipyridamole 22Smg daily in reducing the incidence of coronary artery bypass graft (CABG) reocclusion, which occurred with a frequency of 34% in both treatment groups after I 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 S% compared to IS% 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 haemo­dialysis membranes have found a sigrtificant reduction in membrane occlusion after administra­tion of indobufen 200mg twice daily for 7 days (30%) compared to placebo (S1.S%) 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 I % of those treated). The majority of adverse effects reported during treatment are gastrointestinal and include dyspepsia, abdomimll pain, consti­pation, nausea and vomiting. Haemostasis and coagulation disorders and skin arid 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 indobuf~n 200mg twice daily (9%) compared with aspirin 97Smg daily plus dipyridamole 22Smg daily (18%).

Dosage and Administration

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.

448

Fig. 1. Structural formula of indobufen (2-[p-(l-oxo-2-isoin­dolinyl)-phenyl] butyric acid); * = chiral centre.

Indobufen or [p-(1-oxo-2-isoindolinyl)-phenyl] butyric acid (fig. 1) has been found to have platelet antiaggregatory effects both in vitro and ex vivo and has proven effective in clinical trials for the treat­ment and prophylaxis of coronary, cerebral and peripheral vascular diseases.

1. Pharmacodynamic Properties 1.1 Effects ofIndobufen on Platelet Function

1.1.1 Platelet Thromboxane Synthesis Extrinsic factors such as collagen, thrombin and

epinephrine (adrenaline), which are released at sites of vascular damage, trigger platelet activation and aggregation. Activated platelets synthesise and re­lease compounds such as ADP (adenosine diphos­phate), serotonin (5-hydroxytryptamine) and plate­let derived growth factor (PDGF) which can potentiate platelet aggregation, synthesis and re­lease. Stimulation of arachidonic acid metabolism in platelets initiated by phospholipase A2 is an im­portant pathway in the mechanism of platelet ac­tivation. Thromboxane B2 (TXB2) is a metabolic product of arachidonic acid which has powerful platelet aggregating activity and also acts as a vaso­constrictor.

Indobufen inhibits the stimulatory effect of agonists on platelets by reversibly inhibiting ara­chidonic acid metabolism through inhibition of the platelet cyc1o-oxygenase enzyme (fig. 2), which is important in the production of TXB2, a stable de­rivative of thromboxane A2 (TXA2). Indobufen is an optically active compound with the S-enan­tiomer responsible for the majority of the platelet inhibitory activity; however, studies have found no significant difference in cyc1o-oxygenase inhibitory potency between the racemate and S-indobufen

Drugs 44 (3) 1992

(Cerletti et al. 1990; De Caterina et al. 1992; Pa­trignani et al. 1990).

In vitro and ex vivo analysis of the effects of indobufen on intraplatelet [14C]arachidonic acid metabolism has been examined using high per­formance liquid chromatography (HPLC). Pinto et al. (1987) reported a linear relationship between TXB2 inhibition and log drug concentration (0.015 to 60 JLmolfL) in platelet-rich plasma from healthy volunteers. Indobufen caused inhibition of TXB2 production at very low concentrations, with 50% inhibition occurring at 0.85 JLmolfL and almost complete inhibition at 34 JLmolfL. Oral adminis­tration ofindobufen (200mg twice daily for 3 days) to healthy volunteers was also found to signifi­cantly inhibit platelet TXB2 production induced by thrombin. Maximal inhibition occurred 2 hours after drug administration and was still pronounced (95%) 12 hours after the last dose (Pinto et al. 1987).

Oral indobufen 200mg causes significant ex vivo inhibition of platelet TXB2 production induced by a number of different agonists in healthy volun­teers (table I). Indobufen (10 JLmolfL) had a com­parable inhibitory effect in vitro on platelet TXB2 production induced by ADP, epinephrine and

Membrane phospholipid

P,""phoU"", A, 1 Arachidonic acid

CY'Jo~'yg,oo" 1 .. Cyclic endoperoxides (PGH2. PGG2)

Prostacyclin synthetase

Indobufen inhibits

Fig. 2. Locus of action of indobufen in pathways of platelet arachidonic acid metabolism. Abbreviations: PG = prosta­glandin; TX = thromboxane.

Indobufen: A Review

Table I. Inhibitory effects of indobufen ex vivo (200mg orally)

and in vitro (10 ILmol/L) on agonist-stimulated thromboxane 82

(TX82) production in platelets from healthy volunteers (adapted

from Cattaneo et al. 1987)

Aggregating agent

ADP 4lLmol/L

Epinephrine 10 ILmol/,L

PAF 0.2 ILmol/L

2.0 ILmol/L

Collagen 2 mg/L

4 mg/L

Arachidonic acid 1 mmol/L

2 mmol/L

Inhibition of TX82

production (% of

pretreatment level)

ex vivo in vitro

2.7 1.8

0.1 2.2

1.2 0.9

0.9 1.1

0.1

1.2

2.5

34.7

Abbreviations: ADP = adenosine diphosphate; PAF = platelet

activating factor.

platelet activating factor (PAF). In both studies, in­hibition of TXB2 production induced by 2 mmol/ L arachidonic acid was incomplete, and in the in vitro study 10 p,mol/L indobufen did not cause complete inhibition of collagen-induced TXB2 pro­duction. A concentration of 100 p,mol/L indobufen was required to inhibit the induction of TXB2 by collagen (2 mgjL) by 95%.

The findings that indobufen dose-dependently inhibits intracellular calcium mobilisation and in­hibits inositol trisphosphate formation in collagen­stimulated platelets (Sumi et al. 1990) are also con­sistent with an inhibitory effect of the drug on TXB2 formation through inhibition of platelet cyclo-oxy­genase.

The ex vivo effect of indobufen on platelet TXB2 production in patients with vascular disease has been investigated (Davi et al. 1988; Mannucci et al. 1987; Rebuzzi et al. 1990). The results of these studies are summarised in table II. TXB2 produc­tion during whole blood clotting and in platelet rich plasma from patients with ischaemic heart disease was almost completely inhibited 2 hours after a single oral dose of indobufen 200mg, and this in­hibition was still pronounced at 12 hours postdose (89%) [Davi et al. 1988]. Inhibition was signifi-

449

cantly attenuated (47%) after 24 hours, indicating that the effect of indobufen on cyclo-oxygenase ac­tivity is reversible. Similar results were reported in platelets from patients at high risk of developing atherosclerosis (Mannucci et al. 1987). Collagen­induced platelet TXB2 production was inhibited by more than 90% 2 hours after single oral doses of indobufen (200 or 400mg) and inhibitory activ­ity was diminished but still significant 24 hours after indobufen administration (47% inhibition after 200mg and 70% inhibition after 400mg).

Oral indobufen therapy (100 or 200mg twice daily for 1 week) starting 3 to 10 days after the onset of acute myocardial infarction (n = 12) in­hibited platelet TXB2 production by more than 90% 2 hours after the first dose, and production re­mained depressed throughout the 12 hour duration of the study (Rebuzzi et al. 1990).

1.1.2 Platelet Aggregation Indobufen is an effective inhibitor of platelet ag­

gregation both in vitro and ex vivo in healthy volunteers and patients with ischaemic heart dis­ease. A significant correlation between plasma drug concentrations and antiaggregant activity ex vivo has been observed, with a minimum plasma con­centration of 4 mgfL required to ensure inhibition of aggregation (Tamassia et al. 1979).

The results of studies investigating the ex vivo inhibitory effect of oral indobufen on platelet ag­gregation are reported in table III. Indobufen (200mg) significantly inhibits the secondary wave of aggregation induced by ADP, epinephrine and PAF but has no effect on the primary wave of ag­gregation ind\lced by these agonists, indicating that it does not interfere with their specific pathways of platelet activation (Cattaneo et al. 1987; Davi et al. 1988); Inhibition of collagen- and arachidonic acid- induced aggregation was dose dependent and indobufen ha4 no effect on the irreversible aggre­gation induced by higher concentratidns of PAF (2 p,mol/L).

Maximal ex vivo inhibition of ADP- and col­lagen-induced platelet aggregation was evident 2 hours after indobufen administration and this in­hibition was reversible, with platelet aggregation

450 Drugs 44 (3) 1992

Table II. Ex vivo inhibition of platelet arachidonic acid metabolism determined at various times following oral indobufen administration

to patients with vascular disease or hyperlipidaemia

Reference Patients Indobufen dose Duration of Inhibition of TXB2

(mg) treatment production ("!o) no. disease

characteristics 2h 12h 24h

Davi et a!. (1988) 20 IHD 200 bid 4 weeks 98 89 47

Mannucci et a!. (1987) 16 Ath risk 200 Single dose > 90 47

400 > 90 70

Rebuzzi et al. (1990) 12 AMI 200 bid 1 week > 90 > 90

Abbreviations: AMI = acute myocardial infarction; Ath risk = atherosclerotic risk; bid = twice daily; h = hours; IHD = ischaemic heart

disease.

returning to baseline within 24 hours of adminis­tration of a single 200mg dose (Carrieri & Orefice 1984; Crow et al. 1985; Mannucci et al. 1987; Pog­liani et al. 1981a; Visona et al. 1983; Table III). Inhibition of collagen-induced aggregation was still significant, however, after 24 hours in patients who received a 300 or 400mg dose of indobufen (Man­nucci et al. 1987; Vinazzer & Fuccella 1980). In­dobufen has a similar inhibitory effect on platelet aggregation following single- and multiple-dose administration (Crow et al. 1985; Mannucci et al. 1987).

Platelets from patients with atherosclerotic dis­ease and type IIA hypercholesterolaemia exhibit enhanced aggregability (Nenci et al. 1982; Tremoli et al. 1981; Visona et al. 1983). In a placebo-con­trolled crossover study involving 8 patients with type IIA hypercholesterolaemia and 8 healthy volunteers, platelet aggregation in response to threshold concentrations of epinephrine and ara­chidonic acid was greater in patients with type IIA hypercholesteroiaemia; however, indobufen (200mg twice daily for 3 days) completely suppressed,plate­let aggregation in both patients and healthy con­trols (Tremoli et al. 1981); Lower concentrations of aggregating agents were required to overcome the inhibitory effect of indobufen on platelets from type IIA patients compared with healthy controls.

Nenci et aI. (1982) have used Breddin's platelet aggregation test to study the effects of indobufen on the SDontaneous aruu-eJUltion of platelets in their

normal environment. Administration of indobufen (100 or 200mg twice daily) resulted in prompt nor­malisation of the enhanced platelet aggregation found in 12 patients with atherosclerotic disease. Furthermore, 50% of the patients maintained a normal level of spontaneous platelet aggregation 4 days after discontinuing treatment; a return to baseline activity levels was demonstrable after 8 days.

A similar inhibitory effect of indobufen on spontaneous platelet aggregation in patients with atherosclerosis has been found using the platelet aggregation filtration pressure (P AFP) test (Visona et al. 1983). In this study a single oral or intraven­ous dose of indobufen 200mg markedly reduced platelet aggregation compared with placebo after 2, 4 and 8 hours, with values increasing after 24 hours, and there was no significant difference in potency between the 2 routes of administration.

Platelet sensitivity to aggregating agents in­creases during exercise in patients with stable an­gina. When compared with placebo in a double­blind crossover study, a single oral dose of indob­ufen 200mg markedly inhibited ADP- and colla­gen-induced platelet aggregation (Pogliani et al. 1981 b). Evening administration of indobufen 200mg inhibited the increase in platelet sensitivity to the agonists ADP and collagen which frequently occurs between 6am and 9am in both healthy volunteers and in patients with ischaemic heart disease (Craveri et al. 1989).

Indobufen: A Review

Indobufen administration has been associated with a reduction in levels of circulating platelet ag­gregates in patients with transient cerebral is­chemia (Carrieri et al. 1983). Levels were signifi­cantly reduced within 2 hours of indobufen administration (200mg) and remained significantly depressed after 5 days of treatment.

1.1.3 Platelet Release Reaction Platelets contain dense and alpha secretory

granules, the contents of which are released during platelet aggregation. Alpha granules contain fibrin­ogen, fibronectin, von Willebrand factor, platelet factor 4 (PF4) and beta-thromboglobulin (BTG), and dense granules contain ADP, serotonin, cal­cium and phosphate salts. The release of granule contents is an important factor in platelet activa­tion as the majority of these substances are in­volved in platelet adhesion and aggregation at sites

451

of vascular damage. Indobufen has an inhibitory effect on the platelet release reaction in both in vi­tro and ex vivo studies of human platelets.

ATP release in response to ADP, epinephrine and PAF was inhibited in platelets from healthy volunteers following incubation with indobufen (10 ~mol/L) in vitro (Cattaneo et al. 1987); further­more, agonist-induced ATP release was inhibited ex vivo 2 hours after oral administration of indob­ufen 200mg. Serotonin release from platelets after exercise in patients with angina is also inhibited following indobufen administration (Pogliani et al. 1983).

In a study which used· radioimmunoassay (RIA) to investigate platelet function in 6 healthy volun­teers, Crow et al. (1985) observed a decrease in plasma PF3 levels 2 and 4 hours after a single dose of indobufen 200mg and 12 hours after multiple­dose administration of indobufen (200mg twice

Table III. Ex vivo inhibition of spontaneous and agonist-induced platelet aggregation, determined at various times following oral administration of indobufen to healthy volunteers and patients with vascular disease

Reference Subjects Indobufen Duration of Agonist Inhibition of platelet

dose (mg) treatment aggregation (%) no. characteristics

2h 4h 12h 24h

Cattaneo et al. 8 Healthy 200 Single dose ADP 4/Lmol/L 50 (1987) volunteers Adrenaline 10 /Lmol/L 80

PAF 0.2 /Lmol/L 50 PAF 0.4 /Lmol/L 10 AA 1 mmol/L 92 Collagen 2 mg/L 70

Crow et al. 6 Healthy 200 Single dose Collagen 4 mg/L 60 61 7 (1985) volunteers 200 bid 7 days Collagen 4 mg/L 57 45 0 Davi et al. 8 Healthy 200 Single dose ADP 5/Lmol/L 32 (1988) volunteers PAF 0.5 /Lmol/L 38

AA 0.4 /Lmol/L 87

Collagen 2 mg/L 78

20 IHD 200 bid 4 weeks ADP 3/Lmol/L 28

Adrenaline 0.3 /Lmol/L 44

PAF 0.5 /Lmol/L 35

Collagen 2 mg/ml 38

AA 0.4 /Lmol/L 41 Visona et al. 12 Ath 200 Single dose Spontaneous 32 28 29 15 (1983)

Abbreviations: AA = arachidonic acid; Ath = patients with atherosclerosis; ADP = adenosine diphosphate; bid = twice daily; IHD = patients with ischaemic heart disease; PAF = platelet activating factor.

452

daily for 6 days}. PF4 and BTG plasma levels, de­termined by RIA, were both significantly reduced during indobufen therapy in patients with transient cerebral ischaemia (Carrieri & Orefice 1984; Or­efice et al. 1984), and significant inhibition of PF4 release and PF3 availability has also been reported in patients with vascular disease following single (300mg) or repeated dose (200mg twice daily for ro days) indobufen administration (Ciavarella et al. 1981; Vinazzer & Fuccella 1980).

1.1.4 Platelet Adhesion Platelet adhesion to the subendothelium of the

vessel wall is an important step in the mechanism of platelet aggregation. Although initial in vitro studies found no effect of indobufen on platelet ad­hesiveness to glass microphores, subsequent ex vivo studies have shown indobufen treatment to sig­nificantly decrease platelet adhesiveness (Carrieri & Orefice 1984; Moia et al. 1988; unpublished data on file, Farmitalia Carlo Erba). This was evident both 2 hours after a single oral dose of indobufen (100 to 200mg) and after 5 days treatment in healthy volunteers and in patients with transient cerebral ischaemia. Nenci et al. (1982) have also reported a decrease in platelet adhesion in patients with atherosclerotic disease, although this effect reached statistical significance only at the fourth day of treatment with indobufen 200mg twice daily. Crow et al. (1985) failed to detect any significant difference in platelet adhesion 2 and 4 hours after a single oral dose of indobufen 200mg, and after multiple doses, in healthy volunteers. Platelet ad­hesion to siliconised glass and bovine extracellular matrix was significantly inhibited 1 hour after a single intravenous injectionofindobufen roOmg in patients with peripheral obliterative disease (Bie­lawiec et al. 1991).

1.2 Effects on Blood Coagulation and Erythrocyte Deformability

Bleeding time was significantly prolonged, com­pared with pretreatment values and placebo, in patients with vascular disease receiving indobufen (100 to 200mg twice daily for up to ro days) [Car-

Drugs 44 (3) 1992

rieri & Orefice 1984; Ciavarella et al 1981; Nenci et al. 1982; Pogliani et al. 1981a; Vinazzer & Fuc­cella 1980]. This effect was evident 2, 4 and 8 hours after administration, although values remained within the upper normal limit at all times.

Increased red cell rigidity has been observed in peripheral vascular disease, cerebrovascular dis­ease and in cardiovascular disorders (Dodds et al. 1980; Reid et al. 1976; Sanita 1981). The effect of indobufen on red blood cell deformability has been examined by measuring blood filterability through a micropore filter (Grasselli et al. 1987). In vitro, indobufen had no significant effect on the deform­ability of red blood cells from healthy volunteers. When administered to 14 patients with obstructive vascular disease, however, indobufen (200mg twice daily for 4 weeks) improved red blood cell deform­ability (Grasselli et al. 1987). This improvement was not statistically significant 2 hours after the first administration but a significant effect (p < 0.05) was observed 2 hours after the morning dose when measured on the fifth, fourteenth and twenty­eighth treatment days.

1.3 Effects on Microcirculatory Parameters

Patients suffering from intermittent claudica­tion as a result of peripheral vascular disease have decreased skin blood flow, and the venoarteriolar reflex, which regulates skin blood flow between resting and standing positions, is often impaired. The effects of indobufen on these parameters have been examined using laser-Doppler flowmetry, (Belcaro 1990a,b; Signorini et al. 1988). Signorini et al. (1988) found a significant difference (p < 0.01) in skin blood flow between placebo and indobufen groups, with the indobufen group showing an im­provement and the placebo group showing no change or a deterioration. Indobufen (200mg twice daily) significantly (p < 0.05) increased mean rest­ing skin blood flow (0.55 ml/min) compared with basal levels (0.41 ml/min) after ro days and a sig­nificant improvement (p < 0.05) in the venoarter­iolar reflex was also· found after 10 days' therapy (Belcaro 1990b). The venoarteriolar reflex was fur-

Indobufen: A Review

ther improved after combined treatment with in­dobufen and defibrotide.

The effect of indobufen on microcirculatory parameters in diabetic patients has been investi­gated in a preliminary study (Belcaro et al. 1990c). Twice daily administration of indobufen 200mg for 1 year to 82 patients with diabetic microangiopa­thy resulted in a slight, nonsignificant improve­ment in resting and standing skin blood flow and a significant improvement (p < 0.05) in the veno­arteriolar reflex compared with baseline values (18.2% decrease in flow on standing with indobu­fen vs 16.5% at baseline). These parameters dete­riorated in untreated patients and there was a sig­nificant (p < 0.05) difference between the treated and untreated patients.

1.4 In Vivo Effects in Experimental Models of Thrombosis

Animal model systems have proved useful in the analysis of the antithrombotic properties of in­dobufen in vivo. Using a mouse antithrombotic as­say, Di Minno and Silver (1983) have evaluated and compared the properties of several agents in vivo. In male Swiss-Webster mice, a combination of alcohol (ethanol) 2 glkg and indobufen 0.5 mgf kg provided complete protection against the lethal thrombotic effects of a mixture of collagen and epi­nephrine. Ethanol and indomethacin also provided complete protection, whereas a combination of ethanol and aspirin provided 84% protection.

Animal models have also been used to assess the ability of indobufen to prevent thrombosis fol­lowing vascular surgery. Carrieri et al. (1987) in­vestigated the antithrombotic effect of indobufen following the formation of an end-to-side anasto­mosis between the left and right common carotid arteries in rats. Total occlusion of the anastomosis was found in 8 of 15 untreated rats, whereas in­dobufen completely inhibited thrombus formation in 14 of 15 treated rats. Administration of indob­ufen 200mg twice daily for 2 days prior to surgery was significantly more effective (p < 0.05) than placebo in reducing autologous platelet deposition in femoral artery grafts in dogs, and graft occlusion

453

was prevented for up to 28 days after implantation (Lane et al. 1986).

Using an artificial circulation and blood from healthy volunteers who had received indobufen (200mg twice daily for 1 week), Sheehan et al. (1988) studied the in vitro effect of indobufen on the thrombogenic potential of a 'Dacron' pros­thesis. These investigators observed significant in­hibition of platelet aggregation in blood from in­dobufen-treated patients compared with blood flow from a placebo group, suggesting that indobufen may be an effective antiplatelet agent for use fol­lowing bypass surgery involving these prostheses.

2. Pharmacokinetic Properties

The pharmacokinetic profile of indobufen has been investigated following both oral and intra­venous administration in healthy volunteers. The effects of age and renal disease on the bioavaila­bility and excretion of the drug have also been studied. Concentrations of unchanged indobufen in plasma, and of unchanged and total indobufen in urine, were determined by high-performance li­quid chromatography (HPLC) or gas-liquid chro­matography (GLC). HPLC accurately measures in­dobufen .concentrations above 4.4 mg/L in plasma and GLC accurately measures concentrations above 0.3 mgfL in plasma and above 2.5 mgfL in urine (coefficient of variation 2%).

A summary of results from studies investigating the phaqnacokinetics ofindobufen following single oral administration to healthy volunteers is pre­sented iIi table IV.

2.1 Absorption

Indobufen is rapid1y and almost completely ab­sorbed following oral administration, and peak plasma concentrations (Cmax) are reached within 2 hours (tmax). Following administration ofa range of single doses between 100 and 400mg, maximum plasma concentrations (Cmax) and area under the plasma concentration-time curve (AUC) values were dose related (Fuccella et al. 1979; Tamassia et al. 1979; unpublished data on file, Farmitalia

454 Drugs 44 (3) 1992

Table IV. Pharmacokinetics of indobufen in healthy young volunteers following single oral dose administration

Reference No. of Dose Cmax tmax AUCO-oo t'l2p Uun Utot volunteers (mg) (mg/L) (h) mg/L· h (h) (mg) (mg)

Fuccella et at (1979) 6 100 12.5 1.8 11.39 67.27 Savazzi et at (1984) 6 200 157.4 6.7 Tamassia et al. (1979) 6 100 14.6 1.5 74.8 7.6 13.31 71.25 Unpublished data on file, 9 100 14.9 1.3 81.5 7.9 Farmitalia Carlo Erba 200 26.5 1.2 178.5 7.8

400 48.2 1.8 360.5 8.7

Abbreviations: AUCO-oo = area under the plasma concentration-time curve extrapolated to infinity; Cmax = maximum plasma concentration; tmax = time to achieve Cmax; tv.,B = terminal phase elimination half-life; Uun = urinary excretion of unchanged drug; Ut6t = urinary excretion of total drug.

Carlo Erba). T max was not modified by increasing doses of up to 400mg and ranged from 1.2 to 1.8h. After a single oral dose of indobufen 100mg, Cmax ranged from 12.S to 14.9 mg!L. After IS consec­utive doses of indobufen 100mg twice daily the mean Cmax was 16.7 mg!L and was 29.2 mg!L after 10 consecutive doses of indobufen 200mg twice daily (Savazzi et al. 1986; Tamassia et al. 1979).

Intake of food prior to indobufen administra­tion (1 OOmg) caused a slight but significant (p < 0.01) decrease in the bioavailability of the drug in 6 heahhy volunteers (Tamassia et al. 1979). Mean Cmax values were reduced from 14.61 to 10.24 mg! L in the presence of food, and AUC values de­creased from 74.78 to 64~67 mg!L· h. Absorption of indobufen tablets, determined by urinary excre­tion of unchanged and total indobufen, was not af­fected by the presence of food. This reduction in bioavailability does not appear to have any appre­ciable effect on the pharmacological activity of in­dobufen (Tamassia et al. 1979).

2.2 Distribution and Elimination

Indobufen has a low apparent volume of dis­tribution in humans which is consistent with the high affinity of the drug for plasma proteins (>99% bound to protein). The apparent volume of distri­bution ranged from 13 to ISL with a mean value of 14.SL in S healthy volunteers following a single oral dose of indobufen 100mg (Fuccella et al. 1979).

The curve describing disappearance of indobu-

fen from plasma is biphasic; the terminal phase elimination half-life is 6 to 8 hours in healthy volunteers (table IV). 70 to 80% of the dose of in­dobufen is recovered in urine within 48 hours of administration, with the majority excreted via the kidney as glucuronic acid conjugates and a small percentage (11 to 13%) excreted as unchanged drug (Fuccella et al. 1979; Tamassia et al. 1979). No sig­nificant difference has been reported in excretion rates following oral and intravenous administra­tion, and food intake does not affect renal clear­ance of indobufen (Fuccella et al. 1979; Tamassia et al. 1979). The plasma clearance of the drug was similar following single or repeated administration both in healthy volunteers and in elderly patients with vascular diseases (Savazzi et al 1986; Tamas­sia et al. 1979). No induction or inhibition of me­tabolism of indobufen has been reported.

2.3 Influence of Age and Renal Disease on Pharmacokinetics

Savazzi et al. (1984) studied indobufen elim­ination in 11 patients with renal failure in com­parison with 6 healthy volunteers. Elimination of indobufen was sensitive to the degree of renal in­sufficiency. The plasma clearance of the drug in healthy individuals (creatinine clearance> 100 ml/ min) was 22.3 ml/min and the plasma elimination half-life was 6.7 hours. In patients with moderate­to-severe renal impairment (creatinine clearance < 20 ml/min), plasma clearance was 7.1 ml/min and

Indobufen: A Review

the plasma elimination half-life was increased to 33.1 hours. Thus, dosage reduction is necessary to prevent excessive drug accumulation in these patients (see section 6).

The pharmacokinetics of indobufen were stud­ied in 18 elderly patients (aged between 54 and 81 years) and compared 18 young healthy volunteers following single (200mg) and repeated (200mg twice daily for 5 days) oral administration (Savazzi et al. 1986). The elimination half-life of indobufen was ' higher in elderly patients than in healthy younger volunteers (t1h 11.6-14.4h vs 6-7h) and plasma drug concentrations were correspondingly higher in the elderly group. This is attributed to the age-related decrease in renal function and a similar dosage re­duction to that recommended for patients with renal insufficiency has been recommended in el­derly patients (see section 6).

3. Therapeutic Use

The therapeutic value of indobufen's anti plate­let activity has been examined in patients with oc­clusive coronary, peripheral and cerebral vascular disease. Platelet activation and aggregation are in­volved in the pathogenesis of these vascular dis­orders and their sequelae, including acute myo­cardial infarction, stroke, peripheral arterial occlusion and venous thromboembolism. The in­hibitory effect of indobufen on platelet activation has proven effective in reducing vasoconstriction and vascular occlusion, coronary graft reocclusion and complications in haemodialysis arising from platelet aggregation on the dialysis membrane.

3.1 Treatment of Occlusive Vascular Disease

The efficacy of indobufen in the therapy of in­termittent claudication resulting from peripheral vascular disease has been assessed in a number of clinical trials of variable duration.

Indobufen 200mg twice daily significantly im­proved pain-free walking distance (PFWD) and total walking distance (TWD) in patients with claudication when compared with placebo and baseline values (Be1caro I 990a,b; Signorini et al.

650 ~ 600 .s 550 g 500 .. .!!! 450 "0 Ol 400 c: ',iii 350 .. ~ 300

~ 250 ,~ 200 a. 150

Placebo . Indobufen

455

100~~~---L--~~---L--~-4 __ ~ o 3 6

Treatment duration (months)

Fig. 3. Mean pain-free walking distance of patients with in­termittent claudication during 6-month treatment with in­dobufen 200mg twice daily (n = 28) or placebo (n = 24) [after Signorini et al. 1988].

1988; unpublished data on file, Farmitalia Carlo Erba). The results of these studies are summarised in table V.

Signorini et al. (1988) examined the effeCts of indobufen (200mg twice daily) on PFWD by means of a treadmill exercise test over a 6-month treat­ment period in a double-blind, plac~bo-controlled study (fig. 3). Mean PFWD was significantly in­creased after 6 months in patients receiving indob­ufen (from 153 to 61Om; p < 0.01) and increased, but not significantly, in patients receiving placebo (from 199 to 243m). There was a significant dif­ference (p < 0.01) in mean PFWDs between in­dobufen- and placebo-treated groups after 6 months. In a larger, more recent study, PFWDs were sig­nificantly improved in patients receiving indobu­fen for 6 months (p < 0.01) compared with those receiving placebo (unpublished data on file, Far­mitalia Carlo Erba). Mean PFWDs increased from 138 to 228m following indobufen 200mg twice daily and from 137 to 153m following placebo. Be1caro U990a,b) also reported an improvement in PFWD following treatment with indobufen (200mg twice daily) in a 10-day crossover study with placebo, and a further improvement in this parameter was observed following combined treatment with in­dobufen 200mg and defibrotide 400mg twice daily for 20 days (table V).

456 Drugs 44 (3) 1992

Table V. Studies comparing the effects of indobufen (INB) 200mg twice daily, indobufen 200mg + defibrotide (DF) 400mg twice

daily, aspirin (ASA) 500mg twice daily and placebo (P) in the treatment of patients with intermittent claudication

Reference Study design No. of Treatment Duration of Mean Mean VAR

patients treatment PFWD TWD (%)

(m) (m)

Belcaro (1990a) Nonblind, 18 Baseline 878 1145 4.5

crossover P 10d 956 1250 6.5 INB 20d 1378' 1390' 16.36'

Belcaro (1990b) Nonblind, 22 Baseline 850 1170 7.3

crossover P 10d 890 1160 4.3

INB 10d 1193' 1304' 14.5

INB + DF 20d 1344' 1570' 32.1'

Belcaro & DeSimone Nonrandomised, 204 Baseline 746 1774

(1991) comparative 22 P ly 510 1120

125 INB ly 1073t 1890t 57 ASA ly 703:1: 1520:1:

Signorini et al. (1988) Randomised, 28 Baseline 153

double-blind INB 3mo 357 INB 6mo 610"

24 Baseline 199 P 3mo 253

P 6mo 243

Unpublished data on Multicentre, 154 Baseline 136 237 file, Farmitalia Carlo randomised, P 6mo 153 263 Erba double-blind 148 Baseline 137 245

INB 6mo 227" 316"

Abbreviations: d = days; m = metres; mo = months; PFWD = pain-free walking distance; TWD = total walking distance; VAR = venoarteriolar reflex (% reduction in skin flow on standing compared to resting); y = year; • = p < 0.05 vs placebo; t = p < 0.05 vs baseline; :I: = p < 0.05 vs indobufen; •• = p < 0.01 vs placebo.

A single study has compared indobufen (200mg twice daily) with aspirin (500mg twice daily) and no treatment in 204 patients with intermittent claudication over a I-year period (Belcaro & De Simone 1991; table V). Indobufen was found to significantly (p < 0.05) improve with mean PFWDs and TWOs compared baseline and this improve­ment was significantly (p < 0.05) greater than that achieved by aspirin. Mean PFWD and TWO val­ues were increased from 746 to 1073m and from 1774 to 1890m, respectively, after I year in patients receiving indobufen. It should be noted that the nature of the randomisation controls in this study was uncertain.

In addition to these trials in patients with peri­pheral vascular disease, indobufen therapy has been

associated with a reduction in ischaemic episodes in patients with silent ischaemia in a small (n = 24), nonrandomised study (Pallone et al. 1989). There was a reduction in mean total duration of ischemic episodes and in the mean magnitude of maximum ST segment depression over 3 months in patients receiving indobufen 200mg twice daily compared with patients receiving no treatment; however, the mechanism involved is unclear, and these findings require confirmation in well-con­trolled studies.

3.2 Prophylactic Use in Occlusive Vascular Disease

3.2.1 Arterial Bypass Graft Surgery, Carotid Endarterectomy and Coronary Angioplasty The success of coronary and femoropopliteal ar-

Indobufen: A Review

tery bypass grafts is seriously limited by the de­velopment of graft occlusion. The frequency of oc­clusion in saphenous vein grafts was reported as between 12 and 20% during the first year and 2 to 4% annually for the next 4 or 5 years (Campeau et al. 1983; Grondin et al. 1989). Subsequently, this rate doubles, so that after 10 years approximately 50% of grafts become occluded due to the occur­rence of graft atherosclerosis.

The pathogenesis of the long term development of graft atherosclerosis is unknown; however, platelet aggregation and TXA2 production may ex­plain early thrombosis of the graft and the resulting intimal thickening may be a precursor to athero­sclerosis.

Clinical trials have shown improved graft pat­ency with the use of anti platelet and anticoagulant drugs such as aspirin, ticlopidine and dipyridamole during the first postoperative year (Fuster & Ches­ebro 1985; Limet et al. 1987). Recent studies have found indobufen to be at least as effective in re­ducing the frequency of graft occlusion as other platelet inhibitors.

The effects of indobufen on coronary artery by­pass graft (CABG) patency over 1 year were re­cently examined in a multicentre, randomised, double-blind study of 569 patients (SINBA Group 1991). Daily administration of indobufen 400mg starting 6 hours after surgery was at least as effec­tive as aspirin 900mg plus dipyridamole 225mg daily . in preventing graft occlusion (fig. 4). Early occlusion (within I month) of I or more grafts oc­curred in 22.7% (n = 34) of patients receiving in­dobufen compared with 23.4% (n = 34) in the as­pirin + dipyridamole group, and after I year 34.2% (n = 69) of indobufen-treated patients had graft oc­clusion compared with 34.4% (n = 62) of patients receiving aspirin + dipyridamole (95% confidence limit = 0.65 to 1.56). This initial study has indi­cated that indobufen may improve CABG patency; further investigation in this indication has recently been carried out in a randomised, double-blind study involving 552 patients (unpublished data on file, Farmitalia Carlo Erba). Indobufen 400mg daily improved graft patency to a similar extent as as­pirin 900mg + dipyridamole 225mg daily I year

457

~ 36 . Indobufen

'" 34 o Acetylsalicylic acid :::> U plus dipyridamole 8 32

AI 30 .<: 28 .~ ~U> 26 rf. ";;' -0 24 ",E -0

.~i1 22 <tic a.<tI 20

Early Late

Fig.4. Early (I-month) and late (I-year) CABG occlusion rates in patients treated with indobufen 200mg twice daily or acetylsalicylic acid 325mg plus dipyridamole 75mg thrice daily (after SINBA Group 1991).

after CABG surgery with all grafts patent in 56% of indobufen-treated patients and in 59% of aspi­rin-dipyridamole recipients.

Graft patency following revascularisation of the lower limbs using prosthetic or reversed saphenous vein grafts is significantly affected by thrombotic occlusion. Inhibition of platelet function by a com­bination of aspirin and dipyridamole improves patency rates of femoropopliteal bypass grafts when compared with placebo (Donaldson et al. 1985; Green et al. 1982). The efficacy of indobufen 200mg twice daily has been compared with that of aspirin 300mg plus dipyridamole 75mg thrice daily in the prevention of occlusion in a polytetrafluoroethy­lene (PTFE) graft following administration for I and 12 months (Curti 1989). Graft patency was comparable between treatment groups after 1 month, with mean patency rates of 94.6% in the indobufen-treated patients (n = 56) and 98.3% in patients who received aspirin plus dipyridamole (n = 57). After 1 year of treatment, patency rates were 60.0% and 53.2%, respectively.

Antiplatelet drugs have proven useful in de­creasing the incidence of carotid artery thrombosis following reconstructive surgery for atherosclerotic carotid occlusive disease (Edwards et al. 1985). In­ternal carotid artery occlusion has been reported in approximately 5% of patients during the im­mediate period following surgery and late resten­osis occurs in 1 to 30% of cases (Ortega et al. 1981;

458

Salenius et al. 1989; Stoney & String 1976). In a double-blind, placebo-controlled trial, Pratesi et al. (1991) administered indobufen 400mg daily or pla­cebo to 20 patients undergoing carotid endarter­ectomy, starting 2 days before surgery and contin­uing for 6 months thereafter. Platelet accumulation and aggregation in carotid endarterectomy was as­sessed by means of scintigraphy using 111 In-la­belled platelets. Postoperative scintigraphy failed to detect any significant platelet accumulation or aggregation in patients treated with indobufen whereas this was evident in 4 of 10 patients in the placebo group. Angiographic analysis performed intraoperatively at the end of surgery and venous angiography performed at the end of the study re­vealed 2 patients with stenotic relapse and 1 patient with carotid occlusion in the placebo group but there were no lesions of any significance in the in­dobufen-treated group. While a larger trial is nec­essary to confirm these findings, they suggest that indobufen therapy, starting before surgery and con­tinuing for at least 6 months postsurgery, may help prevent thrombosis following carotid endarterec­tomy.

The effect of indobufen 400mg twice daily or aspirin 325mg 3 times daily on the incidence of recurrent stenosis has been investigated in 323 patients following percutaneous translumina1 cor­onary angiop1asty (Dalla Volta 1989). Both drugs were similarly effective in preventing recurrent ste­nosis over a 6 month period, with 31 % of patients receiving indobufen and 38% of patients receiving aspirin showing restenosis.

3.2.2 Transient Ischaemic Attack and Stroke Thrombotic and embolic complications of ath­

eroma are considered to be the main cause of sev­ere cardiovascular and cerebrovascular events in patients following a transient ischaemic attack (TIA) or mild stroke.

The efficacy of indobufen in the secondary pre­vention of TIA and stroke has been assessed over a 12-month treatment period in a noncomparative study of 270 patients with a history of one or more episodes of TIA within the 3 months prior to the commencement of the study (Rogan et al. 1990).

Drugs 44 (3) 1992

The average incidence and number of recurrent TIAs declined significantly (p < 0.001) after 1 month of therapy with indobufen (lOOmg twice daily) and remained decreased for the remainder of the study. Treatment was not effective in ap­proximately 5% of the patients.

Fornaro et al. (1990) have reported a significant (p < 0.05) decrease in the incidence of fatal and nonfatal thromboembolic events compared with placebo following 26 months of indobufen therapy (lOOmg twice daily) in 196 patients with heart dis­ease (90 with atrial fibrillation and 106 in sinus rhythm). The incidence of events in the indobufen­treated group was 5% compared with 15% in the placebo group. In a nonrandomised retrospective study (Belcaro et al. 1990d), indobufen therapy was associated with a lower incidence of 'new cardiac events' (2.34%) in a group of 638 patients with cerebrovascular disease, compared with a 6% in­cidence in a similar control group of 50 patients who received no treatment. The incidence of events in the indobufen group was also significantly lower than that in patients receiving either aspirin 250mg twice daily (2.8%; n = 265) or dipyridamole 75mg twice daily (2.9%; n = 174) [Belcaro et al. 1990d).

In another study, Rodriguez et al. (1989) failed to find any significant difference in the incidence of new cerebrovascular events between patients re­ceiving either indobufen 200mg twice daily (n = 51) or aspirin 500mg twice daily (n = 52) for a mean of 21 weeks.

These studies suggest that the platelet inhibitory activity of indobufen may improve the prognosis of patients after a transient ischaemic attack or mild stroke.

3.2.3 Deep Vein Thrombosis The efficacy of indobufen in the prevention of

recurrent deep vein thrombosis (DVT) has been investigated over a 3-year period in a randomised trial of 123 patients following an episode of DVT (Belcaro et al. 1992). The incidence of thrombosis in the group of patients receiving indobufen 200mg twice daily was significantly lower (p < 0.02) than in the group receiving no treatment (5 and 46%, respectively).

Indobufen: A Review

The development ofDVT is common in patients following acute myocardial infarction, occurring with an incidence of approximately 30%. Because of the role of platelets in the pathogenesis of thrombosis, the use of indobufen in the prophy­laxis ofDVT has been investigated in patients with acute myocardial infarction, in comparison with the oral anticoagulant acenocoumarol (Peters et al. 1982). In this double-blind prospective study, 150 patients were administered indobufen 200mg twice daily or acenocoumarol for 10 days, starting within . . 24 hours of the acute event. Screenmg for the de-velopment of DVT was by [I25I]-fibrinogen leg scanning. No significant difference was found be­tween the incidence of DVT in indobufen- (11%) and acenocoumarol-treated patients (9%).

These findings suggest that indobufen may be effective in the prophylaxis of DVT and that fur­ther larger studies of the drug in this indication are warranted.

3.2.4 Haemodialysis Platelet adhesion and activation occurs on the

dialysis membrane during haemodialysis in patients with chronic renal failure. The resulting microth­rombus formation leads to a reduction in dialyser efficiency and may contribute to increased blood loss during dialysis. The antiplatelet drugs aspirin and dipyridamole have both shown favourable re­sults in preventing thrombus formation and plate­let deposition on the dialysis membrane (Salter et al. 1985).

Plasma levels of the platelet markers BTG and PF4 are elevated in patients with chronic renal fail­ure and are further increased during haemodialysis (Green et aL 1980; Pogliani et al. 1979). The effect of indobufen on platelet activation during haemo­dialysis has been determined by monitoring plasma levels ofBTG and PF4, and by using scanning elec­tron microscopy to monitor platelet deposition on the membrane (Buccianti et al. 1982;Pogliani et al. 1982; Salter et al. 1985). Intravenous adminis­tration of indobufen (100mg) 30 minutes before starting haemodialysis reduced levels of BTG and PF4 compared with placebo (Pogliani et al. 1982). This reduction was significant after 30 minutes, at

459

which point the BTG levels were 145 JLgjL follow­ing indobufen and 180 JLg/L following placebo A; PF4 levels after indobufen and placebo were 88 and 134 JLg/L, respectively.

In a double-blind crossover study, 18 haemo­dialysis patients received placebo, indobufen 100 or 200mg for 7 days with a washout period of 7 days between treatments (Salter et al. 1985). There was a significant reduction in mean platelet count and a significant increase in. mean BTG levels dur­ing dialysis in the placebo group, whereas both doses of indobufen were equally effective in inhib­iting platelet function. Scanning electron micro­scopy of membranes following treatment found significantly more platelet deposition after placebo administration than after indobufen treatment (p < 0.05), with an average of 51.5% of membrane occluded following placebo and 30% following in­dobufen. There was no significant difference be­tween the effects of the 2 doses of indobufen on platelet deposition.

Indobufen therapy may therefore prove useful during haelDodialysis in preventing platelet aggre­gation on the dialysis membrane, subsequently im­proving the efficiency of the haemodialyser.

3.2.5 Migraine Abnormal platelet activity has been implicated

in the pathogenesis of migraine, and anti platelet agents may be useful in its prophylaxis (Hanning­ton 1981; Steiner et al. 1985). In one initial double­blind, place\>o-controlled study of 62 patients with classic or common migraine, indobufen therapy (200mg twice daily) was associated with a signifi­cant reduction in both the frequency and duration of migraine attacks, suggesting a potential benefit of Ute drug (Carrieri et al. 1988).

4. Tolerability

Indobufen 200mg twice daily has been very well tolerated in the majority of patients during short and l<mg term clinical trials. In a postmarketing surveillance. study conducted by the manufacturer (Lavezzari ,et al. 1989), the adverse effects of in­dobufen were evaluated in more than 5560 patients

460

Fig. 5. Nature of drug-related adverse events (n = 260) in a postmarketing study of 5560 patients receiving indobufen 200mg twice daily for up to 12 months (after Lavezzari et al. 1989). Abbreviations:CNS = central nervous system; GI = gastroin­testinal; Haem. & coag. = haemostasis and coagulation.

with atherosclerotic disease over a 3-month treat­ment period. Adverse effects were reported in 220 patients (3.9%), necessitating treatment withdrawal in 103 patients (1.9%). A broadly similar incidence of adverse effects has been reported in smaller studies of longer duration (Belcaro et al. I 990d; Rogan et al. 1990; SINBA Group, 1991). In these studies indobufen (200mg twice daily) was admin­istered over a 12-month period and incidences of adverse effects ranged between 3.2 and 9%. How­ever, one noncomparative multicentre study re­ported a higher incidence of adverse effects (23%) over a 2-year treatment period in 151 patients with occlusive vascular disease (Italian Multicentre Study Group 1985).

The most commonly reported adverse effects associated with indobufen were gastrointestinal, which accounted for approximately 80% of the total drug-related effects (Italian Multicentre Study Group 1985; fig. 5). These included dyspepsia (32% of total reported effects), abdominal pain (21%), constipation (9%), nausea and vomiting (10%). Haemostasis and coagulation disorders associated with indobufen therapy have been reported in a small number of patients (0.4%). Similarly low in­cidences of skin and CNS disorders have been re­ported (Lavezzari et al. 1989). Haemostatic ad­verse effects accounted for 8%, CNS effects 3% and skin disorders 7% of total adverse effects.

Drugs 44 (3) 1992

In comparative studies in patients with coron­ary and cerebral vascular disease a lower incidence of adverse effects in patients receiving indobufen 200mg twice daily has been apparent compared with the incidence in patients receiving aspirin 350mg plus dipyridamole 75mg 3 times daily (9 and 18%, respectively; SINBA Group 1991). Ad­verse effects in patients receiving indobufen were generally less severe and subsequently the per­centage of patients discontinuing treatment was lower than in the other treatment groups.

5. Drug Interactions

There are few investigations of drug interac­tions involving indobufen. Pretreatment with in­dobufen 200mg twice daily has been reported to significantly (p < 0.05) increase plasma glipizide concentrations after single dose administration of oral glipizide 5mg to 6 healthy volunteers (Elvan­der-Stahl et al. 1984), an effect possibly attribut­able to an inhibitory effect of indobufen on glipi­zide metabolism. This finding implies that dosage adjustment of glipizide may be necessary when co­administered with indobufen.

Indobufen did not influence the pharmacokin­etic properties of the {3-adrenoreceptor antagonists propanolol 80mg or atenolol 100mg when each drug was administered to separate groups of 6 volun­teers (Elvander-Stahl et al. 1984).

6. Dosage and ·Administration

The recommended daily dosage of indobufen is 100 to 200mg orally twice daily after meals.

Dosage reduction to 100mg tWice daily in patients with mild to moderate renal impairment (creatinine clearance 30 to 80 ml/min) and to 100mg once daily in patients with moderate to sev­ere renal impairment (creatinine clearance < 30 ml/ min) is recommended. Similar dose reductions are recommended for the elderly based on creatinine clearance rates.

7. Place of Indohufen in Therapy

Indobufen is a platelet aggregation inhibitor which may be useful in the management of throm­bosis. Studies have shown indobufen to be an ef-

Indobufen: A Review

fective anti platelet agent which, unlike aspmn, causes reversible inhibition of platelet cyclo-oxy­genase, while having no apparent clinically signifi­cant effects on any haemodynamic parameters.

The majority of clinical studies to date have ex­amined the therapeutic efficacy of indobufen in patients with peripheral vascular disease and its prophylactic use in patients following revascular­isation surgery.

Placebo-controlled randomised studies have found a significant and sustained increase in pain­free and total walking distances following indob­ufen therapy in patients with intermittent claudi­cation, and initial findings in a nonrandomised, short term study suggest that indobufen has a more pronounced ameliorative action than aspirin in this setting; however, this observation remains to be confirmed in well-controlled studies. In addition, the relative efficacies of indobufen and ticlopidine in peripheral artery disease remain to be estab­lished.

The clinical significance of the apparent bene­ficial effect of indobufen on microcirculatory para­meters found in studies in patients with peripheral vascular disease or diabetes has yet to be deter­mined.

Indobufen 200mg twice daily appears to be sig­nificantly more effective than placebo in prevent­ing vascular reocclusion following carotid endar­terectomyand femoropopliteal bypass surgery, and at least as effective as aspirin 975mg daily in com­bination with dipyridamole 225mg daily in im­proving coronary artery bypass graft patency.

In addition to its use in the treatment of inter­mittent claudication and prevention of arterial graft occlusion, the efficacy of indobufen for secondary prevention of vascular events following myocard­ial infarction or transient ischaemic attack has been investigated in a small number of controlled stud­ies. While these studies have indicated a potential benefit of indobufen in reducing the incidence of secondary attacks over a 3-year period, further long term studies are required to confirm the prophy­lactic efficacy of indobufen and its influence on patient prognosis.

An initial study has found indobufen therapy to

461

be effective in decreasing the frequency and dur­ation of migraine attacks, suggesting that the drug may have a beneficial effect on the prophylaxis of migraine, and further investigation is warranted. Indobufen may also be effective in the prevention of thrombus formation on haemodialysis mem­branes, a major problem during haemodialysis which results in decreased efficiency and increased blood loss.

Aspirin is currently the most widely used anti­platelet drug; however, adverse effects are fre­quently associated with its use. These effects are mainly gastrointestinal and occur in approximately 10 to 15% of patients receiving aspirin at dosages in excess of300 mg/day. Direct comparisons of the tolerabilities of indobufen and aspirin have found a lower incidence of adverse effects and drug dis­continuation in patients receiving indobufen. It should be noted that in these studies aspirin was administered at high doses (975mg daily) and as aspirin appears to be equally effective at lower doses in the prevention and treatment of occlusive vas­cular disease, a comparison of the incidences of gastrointestinal and haemorrhagic effects following low dose aspirin (150 to 300mg daily) and indob­ufen is required before the relative tolerabilities of the 2 compounds can be properly assessed.

Although indobufen has demonstrated compar­able efficacy to aspirin in improving graft patency rates in patients following revascularisation sur­gery, well-controlled, prospective studies are re­quired to compare the efficacy of the 2 drugs in patients with intermittent claudication.

Thus, initial studies have shown an improve­ment in arterial graft patency associated with in­dobufen and have demonstrated a beneficial effect of the drug in patients with intermittent claudi­cation. Although these findings remain to be con­firmed in larger, well-controlled studies of longer duration, it would seem that indobufen offers po­tential benefits in the therapy and prophylaxis of occlusive vascular disease. Further, because of its low incidence of gastrointestinal and haemorrhagic effects, indobufen may represent a suitable altern­ative to high dose aspirin for long term use in this indication.

462

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Belcaro G. Vasospasm in intermittent claudication. Current Therapeutic Research 48: 667-675, 1990b

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Belcaro G, Pierangeli A, De Simone P. Long-term evaluation of the safety and efficacy of indobufen in cerebrovascular disease. Current Therapeutic Research 47: 444-451, 1990d

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Campeau L, Erijalbert M, Lesperance J, Vaislic C, Grondin CM, et al. Atherosclerosis and late closure of aortocoronary sa­phenous vein grafts: sequential angiographic studies at 2 weeks, I year, 5 to 7 years and 10 to 12 years after surgery. Circulation 68: IIl-II7, 1983

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Carrieri P, Donzelli R, Orefice G, Cerillo A, Volpentesta G, Tay­ana G. Antithrombotic effect ofindobufen in fin experimental model of arterio-arterial microanastomosis in the rat. Throm­bosis Research 45: 195-199, 1987

Carrieri P, Orefice G, Sorge F. A double-blind placebo-controlled trial of indobufen in the prophylaxis of migraine. Acta Neu­rologica Scandinavica 77: 433-436, 1988

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Correspondence: Lynda Wiseman, Adis International Limited. 41 Centorian Drive, Private Bag 65901, Maitangi Bay, Auckland 10, New Zealand.

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