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 Mas sachusetts 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 Es sais 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 Famracol ogiche 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 Summary 448 I. Pharmacodynamic Properties 448 1.1 Effects of Indobufen on Platelet Function 448 1.1.1 Platelet Thromboxane Synthesis 449 1.1.2 Platelet Aggregation 451 1.1.3 Platelet Release Reaction 452 1.1.4 Platelet Adhesion 452 1.2 Effects on Blood Coagulation and Erythrocyte Deformability 453 1.3 Effects on Microcirculatory Parameters 453 1.4 In Vivo Effects in Experimental Models of Thrombosis 453 2. Pharmacokinetic Properties 454 2.1 Absorption 454 2.2 Distribution and Elimination 455 2.3 Influence of Age and Renal Disease on Pharmacokinetics 455 3. Therapeutic Use 455 3.1 Treatment of Occlusive Vascular Disease 457 3.2 Prophylactic Use in Occlusive Vascular Disease 457 3.2.1 Arterial Bypass Graft Surgery, Carotid Endarterectomy and Coronary Angioplasty 458 3.2.2 Transient Ischaemic Attack and Stroke 459 3.2.3 Deep Vein Thrombosis 459 3.2.4 Haemodialysis 460 3.2.5 Migraine 460 4. Tolerability 460 5. Drug Interactions 461 6. Dosage and Administration 461 7. Place of Indobufen in Therapy 446 Drugs 44 (3) 1992
Summary Synopsis 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 throm botic events following transient ischaemic attack or mild stroke and may be effective in the pro phylaxis 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 ofgastrointestinal effects compared to high dose aspirin, rendering indobufen more suit able 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 in dobufen 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 ag gregation 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), sero tonin (5-hydroxytryptamine), platelet factor 3 (PF3), PF4 and J3-thromboglobulin (BTG), de creased 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 throm botic 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 re quired.
Therapeutic Use Indobufen 200mg twice daily improves walking distances in patients with intermittent clau dication. 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, in dobufen 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 sur gery. 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 in dobufen 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 haemo dialysis membranes have found a sigrtificant reduction in membrane occlusion after administra tion of indobufen 200mg twice daily for 7 days (30%) compared to placebo (S1.S%) suggesting that indobufen therapy improves the efficiency of haemodialysis.
Tolerability
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, consti pation, nausea and vomiting. Haemostasis and coagulation disorders and skin arid central nerv ous 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 Drugs 44 (3) 1992
(Cerletti et al. 1990; De Caterina et al. 1992; Pa trignani 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 per Fig. 1. Structural formula of indobufen (2-[p-(l-oxo-2-isoin formance liquid chromatography (HPLC). Pinto et dolinyl)-phenyl] butyric acid); * = chiral centre. al. (1987) reported a linear relationship between TXB2 inhibition and log drug concentration (0.015 Indobufen or [p-(1-oxo-2-isoindolinyl)-phenyl] to 60 JLmolfL) in platelet-rich plasma from healthy butyric acid (fig. 1) has been found to have platelet volunteers. Indobufen caused inhibition of TXB2 antiaggregatory effects both in vitro and ex vivo and production at very low concentrations, with 50% has proven effective in clinical trials for the treat inhibition occurring at 0.85 JLmolfL and almost ment and prophylaxis of coronary, cerebral and complete inhibition at 34 JLmolfL. Oral adminis peripheral vascular diseases. tration ofindobufen (200mg twice daily for 3 days) to healthy volunteers was also found to signifi cantly inhibit platelet TXB2 production induced 1. Pharmacodynamic Properties by thrombin. Maximal inhibition occurred 2 hours 1.1 Effects ofIndobufen on Platelet Function after drug administration and was still pronounced (95%) 12 hours after the last dose (Pinto et al. 1987). 1.1.1 Platelet Thromboxane Synthesis Oral indobufen 200mg causes significant ex vivo Extrinsic factors such as collagen, thrombin and inhibition of platelet TXB2 production induced by epinephrine (adrenaline), which are released at sites a number of different agonists in healthy volun of vascular damage, trigger platelet activation and teers (table I). Indobufen (10 JLmolfL) had a com aggregation. Activated platelets synthesise and re parable inhibitory effect in vitro on platelet TXB2 lease compounds such as ADP (adenosine diphos production induced by ADP, epinephrine and phate), serotonin (5-hydroxytryptamine) and plate let derived growth factor (PDGF) which can Membrane phospholipid potentiate platelet aggregation, synthesis and re lease. Stimulation of arachidonic acid metabolism P,""phoU"", A, in platelets initiated by phospholipase A2 is an im 1 portant pathway in the mechanism of platelet ac tivation. Thromboxane B2 (TXB2) is a metabolic Arachidonic acid product of arachidonic acid which has powerful platelet aggregating activity and also acts as a vaso Indobufen constrictor. CY'Jo~'yg,oo" 1.. inhibits Indobufen inhibits the stimulatory effect of agonists on platelets by reversibly inhibiting ara Cyclic endoperoxides chidonic acid metabolism through inhibition of the (PGH2. PGG2) platelet cyc1o-oxygenase enzyme (fig. 2), which is important in the production of TXB2, a stable de Prostacyclin synthetase rivative of thromboxane A2 (TXA2). Indobufen is an optically active compound with the S-enan tiomer responsible for the majority of the platelet inhibitory activity; however, studies have found no Fig. 2. Locus of action of indobufen in pathways of platelet significant difference in cyc1o-oxygenase inhibitory arachidonic acid metabolism. Abbreviations: PG = prosta potency between the racemate and S-indobufen glandin; TX = thromboxane. Indobufen: A Review 449
Table I. Inhibitory effects of indobufen ex vivo (200mg orally) cantly attenuated (47%) after 24 hours, indicating and in vitro (10 ILmol/L) on agonist-stimulated thromboxane 82 that the effect of indobufen on cyclo-oxygenase ac (TX82) production in platelets from healthy volunteers (adapted tivity is reversible. Similar results were reported in from Cattaneo et al. 1987) platelets from patients at high risk of developing Aggregating agent Inhibition of TX82 atherosclerosis (Mannucci et al. 1987). Collagen production (% of induced platelet TXB2 production was inhibited pretreatment level) by more than 90% 2 hours after single oral doses ex vivo in vitro of indobufen (200 or 400mg) and inhibitory activ ity was diminished but still significant 24 hours after ADP 4lLmol/L 2.7 1.8 indobufen administration (47% inhibition after Epinephrine 10 ILmol/,L 0.1 2.2 PAF 0.2 ILmol/L 1.2 0.9 200mg and 70% inhibition after 400mg). 2.0 ILmol/L 0.9 1.1 Oral indobufen therapy (100 or 200mg twice Collagen 2 mg/L 0.1 daily for 1 week) starting 3 to 10 days after the 4 mg/L 1.2 onset of acute myocardial infarction (n = 12) in Arachidonic acid 1 mmol/L 2.5 hibited platelet TXB2 production by more than 90% 2 mmol/L 34.7 2 hours after the first dose, and production re Abbreviations: ADP = adenosine diphosphate; PAF = platelet mained depressed throughout the 12 hour duration activating factor. of the study (Rebuzzi et al. 1990).
1.1.2 Platelet Aggregation platelet activating factor (PAF). In both studies, in Indobufen is an effective inhibitor of platelet ag hibition of TXB2 production induced by 2 mmol/ gregation both in vitro and ex vivo in healthy L arachidonic acid was incomplete, and in the in volunteers and patients with ischaemic heart dis vitro study 10 p,mol/L indobufen did not cause ease. A significant correlation between plasma drug complete inhibition of collagen-induced TXB2 pro concentrations and antiaggregant activity ex vivo duction. A concentration of 100 p,mol/L indobufen has been observed, with a minimum plasma con was required to inhibit the induction of TXB2 by centration of 4 mgfL required to ensure inhibition collagen (2 mgjL) by 95%. of aggregation (Tamassia et al. 1979). The findings that indobufen dose-dependently The results of studies investigating the ex vivo inhibits intracellular calcium mobilisation and in inhibitory effect of oral indobufen on platelet ag hibits inositol trisphosphate formation in collagen gregation are reported in table III. Indobufen stimulated platelets (Sumi et al. 1990) are also con (200mg) significantly inhibits the secondary wave sistent with an inhibitory effect of the drug on TXB2 of aggregation induced by ADP, epinephrine and formation through inhibition of platelet cyclo-oxy PAF but has no effect on the primary wave of ag genase. gregation ind\lced by these agonists, indicating that The ex vivo effect of indobufen on platelet TXB2 it does not interfere with their specific pathways of production in patients with vascular disease has platelet activation (Cattaneo et al. 1987; Davi et been investigated (Davi et al. 1988; Mannucci et al. 1988); Inhibition of collagen- and arachidonic al. 1987; Rebuzzi et al. 1990). The results of these acid- induced aggregation was dose dependent and studies are summarised in table II. TXB2 produc indobufen ha4 no effect on the irreversible aggre tion during whole blood clotting and in platelet rich gation induced by higher concentratidns of PAF (2 plasma from patients with ischaemic heart disease p,mol/L). was almost completely inhibited 2 hours after a Maximal ex vivo inhibition of ADP- and col single oral dose of indobufen 200mg, and this in lagen-induced platelet aggregation was evident 2 hibition was still pronounced at 12 hours postdose hours after indobufen administration and this in (89%) [Davi et al. 1988]. Inhibition was signifi- hibition 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 adminis normal environment. Administration of indobufen tration of a single 200mg dose (Carrieri & Orefice (100 or 200mg twice daily) resulted in prompt nor 1984; Crow et al. 1985; Mannucci et al. 1987; Pog malisation of the enhanced platelet aggregation liani et al. 1981a; Visona et al. 1983; Table III). found in 12 patients with atherosclerotic disease. Inhibition of collagen-induced aggregation was still Furthermore, 50% of the patients maintained a significant, however, after 24 hours in patients who normal level of spontaneous platelet aggregation 4 received a 300 or 400mg dose of indobufen (Man days after discontinuing treatment; a return to nucci et al. 1987; Vinazzer & Fuccella 1980). In baseline activity levels was demonstrable after 8 dobufen has a similar inhibitory effect on platelet days. aggregation following single- and multiple-dose A similar inhibitory effect of indobufen on administration (Crow et al. 1985; Mannucci et al. spontaneous platelet aggregation in patients with 1987). atherosclerosis has been found using the platelet Platelets from patients with atherosclerotic dis aggregation filtration pressure (PAFP) test (Visona ease and type IIA hypercholesterolaemia exhibit et al. 1983). In this study a single oral or intraven enhanced aggregability (Nenci et al. 1982; Tremoli ous dose of indobufen 200mg markedly reduced et al. 1981; Visona et al. 1983). In a placebo-con platelet aggregation compared with placebo after 2, trolled crossover study involving 8 patients with 4 and 8 hours, with values increasing after 24 hours, type IIA hypercholesterolaemia and 8 healthy and there was no significant difference in potency volunteers, platelet aggregation in response to between the 2 routes of administration. threshold concentrations of epinephrine and ara Platelet sensitivity to aggregating agents in chidonic acid was greater in patients with type IIA creases during exercise in patients with stable an hypercholesteroiaemia; however, indobufen (200mg gina. When compared with placebo in a double twice daily for 3 days) completely suppressed,plate blind crossover study, a single oral dose of indob let aggregation in both patients and healthy con ufen 200mg markedly inhibited ADP- and colla trols (Tremoli et al. 1981); Lower concentrations gen-induced platelet aggregation (Pogliani et al. of aggregating agents were required to overcome 1981 b). Evening administration of indobufen the inhibitory effect of indobufen on platelets from 200mg inhibited the increase in platelet sensitivity type IIA patients compared with healthy controls. to the agonists ADP and collagen which frequently Nenci et aI. (1982) have used Breddin's platelet occurs between 6am and 9am in both healthy aggregation test to study the effects of indobufen volunteers and in patients with ischaemic heart on the SDontaneous aruu-eJUltion of platelets in their disease (Craveri et al. 1989). Indobufen: A Review 451
Indobufen administration has been associated of vascular damage. Indobufen has an inhibitory with a reduction in levels of circulating platelet ag effect on the platelet release reaction in both in vi gregates in patients with transient cerebral is tro and ex vivo studies of human platelets. chemia (Carrieri et al. 1983). Levels were signifi ATP release in response to ADP, epinephrine cantly reduced within 2 hours of indobufen and PAF was inhibited in platelets from healthy administration (200mg) and remained significantly volunteers following incubation with indobufen (10 depressed after 5 days of treatment. ~mol/L) in vitro (Cattaneo et al. 1987); further more, agonist-induced ATP release was inhibited 1.1.3 Platelet Release Reaction ex vivo 2 hours after oral administration of indob Platelets contain dense and alpha secretory ufen 200mg. Serotonin release from platelets after granules, the contents of which are released during exercise in patients with angina is also inhibited platelet aggregation. Alpha granules contain fibrin following indobufen administration (Pogliani et al. ogen, fibronectin, von Willebrand factor, platelet 1983). factor 4 (PF4) and beta-thromboglobulin (BTG), In a study which used· radioimmunoassay (RIA) and dense granules contain ADP, serotonin, cal to investigate platelet function in 6 healthy volun cium and phosphate salts. The release of granule teers, Crow et al. (1985) observed a decrease in contents is an important factor in platelet activa plasma PF3 levels 2 and 4 hours after a single dose tion as the majority of these substances are in of indobufen 200mg and 12 hours after multiple volved in platelet adhesion and aggregation at sites dose 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 Drugs 44 (3) 1992
daily for 6 days}. PF4 and BTG plasma levels, de rieri & Orefice 1984; Ciavarella et al 1981; Nenci termined by RIA, were both significantly reduced et al. 1982; Pogliani et al. 1981a; Vinazzer & Fuc during indobufen therapy in patients with transient cella 1980]. This effect was evident 2, 4 and 8 hours cerebral ischaemia (Carrieri & Orefice 1984; Or after administration, although values remained efice et al. 1984), and significant inhibition of PF4 within the upper normal limit at all times. release and PF3 availability has also been reported Increased red cell rigidity has been observed in in patients with vascular disease following single peripheral vascular disease, cerebrovascular dis (300mg) or repeated dose (200mg twice daily for ease and in cardiovascular disorders (Dodds et al. ro days) indobufen administration (Ciavarella et 1980; Reid et al. 1976; Sanita 1981). The effect of al. 1981; Vinazzer & Fuccella 1980). indobufen on red blood cell deformability has been examined by measuring blood filterability through 1.1.4 Platelet Adhesion a micropore filter (Grasselli et al. 1987). In vitro, Platelet adhesion to the subendothelium of the indobufen had no significant effect on the deform vessel wall is an important step in the mechanism ability of red blood cells from healthy volunteers. of platelet aggregation. Although initial in vitro When administered to 14 patients with obstructive studies found no effect of indobufen on platelet ad vascular disease, however, indobufen (200mg twice hesiveness to glass microphores, subsequent ex vivo daily for 4 weeks) improved red blood cell deform studies have shown indobufen treatment to sig ability (Grasselli et al. 1987). This improvement nificantly decrease platelet adhesiveness (Carrieri was not statistically significant 2 hours after the & Orefice 1984; Moia et al. 1988; unpublished data first administration but a significant effect (p < on file, Farmitalia Carlo Erba). This was evident 0.05) was observed 2 hours after the morning dose both 2 hours after a single oral dose of indobufen when measured on the fifth, fourteenth and twenty (100 to 200mg) and after 5 days treatment in eighth treatment days. healthy volunteers and in patients with transient cerebral ischaemia. Nenci et al. (1982) have also 1.3 Effects on Microcirculatory Parameters reported a decrease in platelet adhesion in patients with atherosclerotic disease, although this effect reached statistical significance only at the fourth Patients suffering from intermittent claudica day of treatment with indobufen 200mg twice daily. tion as a result of peripheral vascular disease have Crow et al. (1985) failed to detect any significant decreased skin blood flow, and the venoarteriolar difference in platelet adhesion 2 and 4 hours after reflex, which regulates skin blood flow between a single oral dose of indobufen 200mg, and after resting and standing positions, is often impaired. multiple doses, in healthy volunteers. Platelet ad The effects of indobufen on these parameters have hesion to siliconised glass and bovine extracellular been examined using laser-Doppler flowmetry, matrix was significantly inhibited 1 hour after a (Belcaro 1990a,b; Signorini et al. 1988). Signorini single intravenous injectionofindobufen roOmg in et al. (1988) found a significant difference (p < 0.01) patients with peripheral obliterative disease (Bie in skin blood flow between placebo and indobufen lawiec et al. 1991). groups, with the indobufen group showing an im provement and the placebo group showing no 1.2 Effects on Blood Coagulation and change or a deterioration. Indobufen (200mg twice Erythrocyte Deformability daily) significantly (p < 0.05) increased mean rest ing skin blood flow (0.55 ml/min) compared with Bleeding time was significantly prolonged, com basal levels (0.41 ml/min) after ro days and a sig pared with pretreatment values and placebo, in nificant improvement (p < 0.05) in the venoarter patients with vascular disease receiving indobufen iolar reflex was also· found after 10 days' therapy (100 to 200mg twice daily for up to ro days) [Car- (Belcaro 1990b). The venoarteriolar reflex was fur- Indobufen: A Review 453
ther improved after combined treatment with in was prevented for up to 28 days after implantation dobufen and defibrotide. (Lane et al. 1986). The effect of indobufen on microcirculatory Using an artificial circulation and blood from parameters in diabetic patients has been investi healthy volunteers who had received indobufen gated in a preliminary study (Belcaro et al. 1990c). (200mg twice daily for 1 week), Sheehan et al. Twice daily administration of indobufen 200mg for (1988) studied the in vitro effect of indobufen on 1 year to 82 patients with diabetic microangiopa the thrombogenic potential of a 'Dacron' pros thy resulted in a slight, nonsignificant improve thesis. These investigators observed significant in ment in resting and standing skin blood flow and hibition of platelet aggregation in blood from in a significant improvement (p < 0.05) in the veno dobufen-treated patients compared with blood flow arteriolar reflex compared with baseline values from a placebo group, suggesting that indobufen (18.2% decrease in flow on standing with indobu may be an effective antiplatelet agent for use fol fen vs 16.5% at baseline). These parameters dete lowing bypass surgery involving these prostheses. riorated in untreated patients and there was a sig nificant (p < 0.05) difference between the treated 2. Pharmacokinetic Properties and untreated patients. The pharmacokinetic profile of indobufen has 1.4 In Vivo Effects in Experimental been investigated following both oral and intra Models of Thrombosis venous administration in healthy volunteers. The effects of age and renal disease on the bioavaila Animal model systems have proved useful in bility and excretion of the drug have also been the analysis of the antithrombotic properties of in studied. Concentrations of unchanged indobufen dobufen in vivo. Using a mouse antithrombotic as in plasma, and of unchanged and total indobufen say, Di Minno and Silver (1983) have evaluated in urine, were determined by high-performance li and compared the properties of several agents in quid chromatography (HPLC) or gas-liquid chro vivo. In male Swiss-Webster mice, a combination matography (GLC). HPLC accurately measures in of alcohol (ethanol) 2 glkg and indobufen 0.5 mgf dobufen .concentrations above 4.4 mg/L in plasma kg provided complete protection against the lethal and GLC accurately measures concentrations above thrombotic effects of a mixture of collagen and epi 0.3 mgfL in plasma and above 2.5 mgfL in urine nephrine. Ethanol and indomethacin also provided (coefficient of variation 2%). complete protection, whereas a combination of A summary of results from studies investigating ethanol and aspirin provided 84% protection. the phaqnacokinetics ofindobufen following single Animal models have also been used to assess oral administration to healthy volunteers is pre the ability of indobufen to prevent thrombosis fol sented iIi table IV. lowing vascular surgery. Carrieri et al. (1987) in vestigated the antithrombotic effect of indobufen 2.1 Absorption following the formation of an end-to-side anasto mosis between the left and right common carotid Indobufen is rapid1y and almost completely ab arteries in rats. Total occlusion of the anastomosis sorbed following oral administration, and peak was found in 8 of 15 untreated rats, whereas in plasma concentrations (Cmax) are reached within dobufen completely inhibited thrombus formation 2 hours (tmax). Following administration ofa range in 14 of 15 treated rats. Administration of indob of single doses between 100 and 400mg, maximum ufen 200mg twice daily for 2 days prior to surgery plasma concentrations (Cmax) and area under the was significantly more effective (p < 0.05) than plasma concentration-time curve (AUC) values placebo in reducing autologous platelet deposition were dose related (Fuccella et al. 1979; Tamassia in femoral artery grafts in dogs, and graft occlusion 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 fen from plasma is biphasic; the terminal phase doses of up to 400mg and ranged from 1.2 to 1.8h. elimination half-life is 6 to 8 hours in healthy After a single oral dose of indobufen 100mg, Cmax volunteers (table IV). 70 to 80% of the dose of in ranged from 12.S to 14.9 mg!L. After IS consec dobufen is recovered in urine within 48 hours of utive doses of indobufen 100mg twice daily the administration, with the majority excreted via the mean Cmax was 16.7 mg!L and was 29.2 mg!L after kidney as glucuronic acid conjugates and a small 10 consecutive doses of indobufen 200mg twice percentage (11 to 13%) excreted as unchanged drug daily (Savazzi et al. 1986; Tamassia et al. 1979). (Fuccella et al. 1979; Tamassia et al. 1979). No sig Intake of food prior to indobufen administra nificant difference has been reported in excretion tion (1 OOmg) caused a slight but significant (p < rates following oral and intravenous administra 0.01) decrease in the bioavailability of the drug in tion, and food intake does not affect renal clear 6 heahhy volunteers (Tamassia et al. 1979). Mean ance of indobufen (Fuccella et al. 1979; Tamassia Cmax values were reduced from 14.61 to 10.24 mg! et al. 1979). The plasma clearance of the drug was L in the presence of food, and AUC values de similar following single or repeated administration creased from 74.78 to 64~67 mg!L· h. Absorption both in healthy volunteers and in elderly patients of indobufen tablets, determined by urinary excre with vascular diseases (Savazzi et al 1986; Tamas tion of unchanged and total indobufen, was not af sia et al. 1979). No induction or inhibition of me fected by the presence of food. This reduction in tabolism of indobufen has been reported. bioavailability does not appear to have any appre ciable effect on the pharmacological activity of in 2.3 Influence of Age and Renal Disease dobufen (Tamassia et al. 1979). on Pharmacokinetics
2.2 Distribution and Elimination Savazzi et al. (1984) studied indobufen elim ination in 11 patients with renal failure in com Indobufen has a low apparent volume of dis parison with 6 healthy volunteers. Elimination of tribution in humans which is consistent with the indobufen was sensitive to the degree of renal in high affinity of the drug for plasma proteins (>99% sufficiency. The plasma clearance of the drug in bound to protein). The apparent volume of distri healthy individuals (creatinine clearance> 100 ml/ bution ranged from 13 to ISL with a mean value min) was 22.3 ml/min and the plasma elimination of 14.SL in S healthy volunteers following a single half-life was 6.7 hours. In patients with moderate oral dose of indobufen 100mg (Fuccella et al. 1979). to-severe renal impairment (creatinine clearance < The curve describing disappearance of indobu- 20 ml/min), plasma clearance was 7.1 ml/min and Indobufen: A Review 455
the plasma elimination half-life was increased to 650 Placebo 33.1 hours. Thus, dosage reduction is necessary to ~ 600 . Indobufen prevent excessive drug accumulation in these .s 550 g 500 patients (see section 6). .. .!!! 450 The pharmacokinetics of indobufen were stud "0 Ol 400 ied in 18 elderly patients (aged between 54 and 81 c: ',iii.. 350 years) and compared 18 young healthy volunteers ~ 300 following single (200mg) and repeated (200mg twice ~ 250 daily for 5 days) oral administration (Savazzi et al. , ~ 200 1986). The elimination half-life of indobufen was ' a. 150 higher in elderly patients than in healthy younger 100 ~~~---L--~~---L--~-4 __~ o 3 6 volunteers (t1h 11.6-14.4h vs 6-7h) and plasma drug Treatment duration (months) concentrations were correspondingly higher in the elderly group. This is attributed to the age-related Fig. 3. Mean pain-free walking distance of patients with in decrease in renal function and a similar dosage re termittent claudication during 6-month treatment with in duction to that recommended for patients with dobufen 200mg twice daily (n = 28) or placebo (n = 24) [after Signorini et al. 1988]. renal insufficiency has been recommended in el derly patients (see section 6). 1988; unpublished data on file, Farmitalia Carlo 3. Therapeutic Use Erba). The results of these studies are summarised in table V. The therapeutic value of indobufen's anti plate Signorini et al. (1988) examined the effeCts of let activity has been examined in patients with oc indobufen (200mg twice daily) on PFWD by means clusive coronary, peripheral and cerebral vascular of a treadmill exercise test over a 6-month treat disease. Platelet activation and aggregation are in ment period in a double-blind, plac~bo-controlled volved in the pathogenesis of these vascular dis study (fig. 3). Mean PFWD was significantly in orders and their sequelae, including acute myo creased after 6 months in patients receiving indob cardial infarction, stroke, peripheral arterial ufen (from 153 to 61Om; p < 0.01) and increased, occlusion and venous thromboembolism. The in but not significantly, in patients receiving placebo hibitory effect of indobufen on platelet activation (from 199 to 243m). There was a significant dif has proven effective in reducing vasoconstriction ference (p < 0.01) in mean PFWDs between in and vascular occlusion, coronary graft reocclusion dobufen- and placebo-treated groups after 6 months. and complications in haemodialysis arising from In a larger, more recent study, PFWDs were sig platelet aggregation on the dialysis membrane. nificantly improved in patients receiving indobu fen for 6 months (p < 0.01) compared with those 3.1 Treatment of Occlusive Vascular Disease receiving placebo (unpublished data on file, Far mitalia Carlo Erba). Mean PFWDs increased from The efficacy of indobufen in the therapy of in 138 to 228m following indobufen 200mg twice daily termittent claudication resulting from peripheral and from 137 to 153m following placebo. Be1caro vascular disease has been assessed in a number of U990a,b) also reported an improvement in PFWD clinical trials of variable duration. following treatment with indobufen (200mg twice Indobufen 200mg twice daily significantly im daily) in a 10-day crossover study with placebo, proved pain-free walking distance (PFWD) and and a further improvement in this parameter was total walking distance (TWD) in patients with observed following combined treatment with in claudication when compared with placebo and dobufen 200mg and defibrotide 400mg twice daily baseline values (Be1caro I 990a,b; Signorini et al. 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 associated with a reduction in ischaemic episodes twice daily) with aspirin (500mg twice daily) and in patients with silent ischaemia in a small (n = no treatment in 204 patients with intermittent 24), nonrandomised study (Pallone et al. 1989). claudication over a I-year period (Belcaro & De There was a reduction in mean total duration of Simone 1991; table V). Indobufen was found to ischemic episodes and in the mean magnitude of significantly (p < 0.05) improve with mean PFWDs maximum ST segment depression over 3 months and TWOs compared baseline and this improve in patients receiving indobufen 200mg twice daily ment was significantly (p < 0.05) greater than that compared with patients receiving no treatment; achieved by aspirin. Mean PFWD and TWO val however, the mechanism involved is unclear, and ues were increased from 746 to 1073m and from these findings require confirmation in well-con 1774 to 1890m, respectively, after I year in patients trolled studies. receiving indobufen. It should be noted that the 3.2 Prophylactic Use in Occlusive nature of the randomisation controls in this study Vascular Disease was uncertain. 3.2.1 Arterial Bypass Graft Surgery, Carotid In addition to these trials in patients with peri Endarterectomy and Coronary Angioplasty pheral vascular disease, indobufen therapy has been The success of coronary and femoropopliteal ar- Indobufen: A Review 457
tery bypass grafts is seriously limited by the de 36 . Indobufen ~ velopment of graft occlusion. The frequency of oc o Acetylsalicylic acid '":::> 34 U plus dipyridamole clusion in saphenous vein grafts was reported as 8 32 between 12 and 20% during the first year and 2 to AI 30 4% annually for the next 4 or 5 years (Campeau et .<: .~ 28 al. 1983; Grondin et al. 1989). Subsequently, this ~U> rf. ";;' 26 -0 rate doubles, so that after 10 years approximately ",E 24 -0 50% of grafts become occluded due to the occur .~i1 22
Salenius et al. 1989; Stoney & String 1976). In a The average incidence and number of recurrent double-blind, placebo-controlled trial, Pratesi et al. TIAs declined significantly (p < 0.001) after 1 (1991) administered indobufen 400mg daily or pla month of therapy with indobufen (lOOmg twice cebo to 20 patients undergoing carotid endarter daily) and remained decreased for the remainder ectomy, starting 2 days before surgery and contin of the study. Treatment was not effective in ap uing for 6 months thereafter. Platelet accumulation proximately 5% of the patients. and aggregation in carotid endarterectomy was as Fornaro et al. (1990) have reported a significant sessed by means of scintigraphy using 111 In-la (p < 0.05) decrease in the incidence of fatal and belled platelets. Postoperative scintigraphy failed nonfatal thromboembolic events compared with to detect any significant platelet accumulation or placebo following 26 months of indobufen therapy aggregation in patients treated with indobufen (lOOmg twice daily) in 196 patients with heart dis whereas this was evident in 4 of 10 patients in the ease (90 with atrial fibrillation and 106 in sinus placebo group. Angiographic analysis performed rhythm). The incidence of events in the indobufen intraoperatively at the end of surgery and venous treated group was 5% compared with 15% in the angiography performed at the end of the study re placebo group. In a nonrandomised retrospective vealed 2 patients with stenotic relapse and 1 patient study (Belcaro et al. 1990d), indobufen therapy was with carotid occlusion in the placebo group but associated with a lower incidence of 'new cardiac there were no lesions of any significance in the in events' (2.34%) in a group of 638 patients with dobufen-treated group. While a larger trial is nec cerebrovascular disease, compared with a 6% in essary to confirm these findings, they suggest that cidence in a similar control group of 50 patients indobufen therapy, starting before surgery and con who received no treatment. The incidence of events tinuing for at least 6 months postsurgery, may help in the indobufen group was also significantly lower prevent thrombosis following carotid endarterec than that in patients receiving either aspirin 250mg tomy. twice daily (2.8%; n = 265) or dipyridamole 75mg The effect of indobufen 400mg twice daily or twice daily (2.9%; n = 174) [Belcaro et al. 1990d). aspirin 325mg 3 times daily on the incidence of In another study, Rodriguez et al. (1989) failed recurrent stenosis has been investigated in 323 to find any significant difference in the incidence patients following percutaneous translumina1 cor of new cerebrovascular events between patients re onary angiop1asty (Dalla Volta 1989). Both drugs ceiving either indobufen 200mg twice daily (n = were similarly effective in preventing recurrent ste 51) or aspirin 500mg twice daily (n = 52) for a nosis over a 6 month period, with 31 % of patients mean of 21 weeks. receiving indobufen and 38% of patients receiving These studies suggest that the platelet inhibitory aspirin showing restenosis. activity of indobufen may improve the prognosis of patients after a transient ischaemic attack or mild 3.2.2 Transient Ischaemic Attack and Stroke stroke. Thrombotic and embolic complications of ath eroma are considered to be the main cause of sev 3.2.3 Deep Vein Thrombosis ere cardiovascular and cerebrovascular events in The efficacy of indobufen in the prevention of patients following a transient ischaemic attack recurrent deep vein thrombosis (DVT) has been (TIA) or mild stroke. investigated over a 3-year period in a randomised The efficacy of indobufen in the secondary pre trial of 123 patients following an episode of DVT vention of TIA and stroke has been assessed over (Belcaro et al. 1992). The incidence of thrombosis a 12-month treatment period in a noncomparative in the group of patients receiving indobufen 200mg study of 270 patients with a history of one or more twice daily was significantly lower (p < 0.02) than episodes of TIA within the 3 months prior to the in the group receiving no treatment (5 and 46%, commencement of the study (Rogan et al. 1990). respectively). Indobufen: A Review 459
The development ofDVT is common in patients which point the BTG levels were 145 JLgjL follow following acute myocardial infarction, occurring ing indobufen and 180 JLg/L following placebo A; with an incidence of approximately 30%. Because PF4 levels after indobufen and placebo were 88 and of the role of platelets in the pathogenesis of 134 JLg/L, respectively. thrombosis, the use of indobufen in the prophy In a double-blind crossover study, 18 haemo laxis ofDVT has been investigated in patients with dialysis patients received placebo, indobufen 100 acute myocardial infarction, in comparison with or 200mg for 7 days with a washout period of 7 the oral anticoagulant acenocoumarol (Peters et al. days between treatments (Salter et al. 1985). There 1982). In this double-blind prospective study, 150 was a significant reduction in mean platelet count patients were administered indobufen 200mg twice and a significant increase in. mean BTG levels dur daily or acenocoumarol for 10 days, starting. within ing dialysis in the placebo group, whereas both 24 hours of. the acute event. Screenmg for the de- doses of indobufen were equally effective in inhib velopment of DVT was by [I25I]-fibrinogen leg iting platelet function. Scanning electron micro scanning. No significant difference was found be scopy of membranes following treatment found tween the incidence of DVT in indobufen- (11%) significantly more platelet deposition after placebo and acenocoumarol-treated patients (9%). administration than after indobufen treatment (p These findings suggest that indobufen may be < 0.05), with an average of 51.5% of membrane effective in the prophylaxis of DVT and that fur occluded following placebo and 30% following in ther larger studies of the drug in this indication are dobufen. There was no significant difference be warranted. tween the effects of the 2 doses of indobufen on platelet deposition. 3.2.4 Haemodialysis Indobufen therapy may therefore prove useful Platelet adhesion and activation occurs on the during haelDodialysis in preventing platelet aggre dialysis membrane during haemodialysis in patients gation on the dialysis membrane, subsequently im with chronic renal failure. The resulting microth proving the efficiency of the haemodialyser. rombus formation leads to a reduction in dialyser efficiency and may contribute to increased blood 3.2.5 Migraine loss during dialysis. The antiplatelet drugs aspirin Abnormal platelet activity has been implicated and dipyridamole have both shown favourable re in the pathogenesis of migraine, and anti platelet sults in preventing thrombus formation and plate agents may be useful in its prophylaxis (Hanning let deposition on the dialysis membrane (Salter et ton 1981; Steiner et al. 1985). In one initial double al. 1985). blind, place\>o-controlled study of 62 patients with Plasma levels of the platelet markers BTG and classic or common migraine, indobufen therapy PF4 are elevated in patients with chronic renal fail (200mg twice daily) was associated with a signifi ure and are further increased during haemodialysis cant reduction in both the frequency and duration (Green et aL 1980; Pogliani et al. 1979). The effect of migraine attacks, suggesting a potential benefit of indobufen on platelet activation during haemo of Ute drug (Carrieri et al. 1988). dialysis has been determined by monitoring plasma levels ofBTG and PF4, and by using scanning elec 4. Tolerability tron microscopy to monitor platelet deposition on the membrane (Buccianti et al. 1982;Pogliani et Indobufen 200mg twice daily has been very well al. 1982; Salter et al. 1985). Intravenous adminis tolerated in the majority of patients during short tration of indobufen (100mg) 30 minutes before and l In comparative studies in patients with coron ary 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). Ad verse effects in patients receiving indobufen were generally less severe and subsequently the per centage of patients discontinuing treatment was lower than in the other treatment groups. Fig. 5. Nature of drug-related adverse events (n = 260) in a postmarketing study of 5560 patients receiving indobufen 5. Drug Interactions 200mg twice daily for up to 12 months (after Lavezzari et There are few investigations of drug interac al. 1989). Abbreviations:CNS = central nervous system; GI = gastroin tions involving indobufen. Pretreatment with in testinal; Haem. & coag. = haemostasis and coagulation. dobufen 200mg twice daily has been reported to significantly (p < 0.05) increase plasma glipizide with atherosclerotic disease over a 3-month treat concentrations after single dose administration of ment period. Adverse effects were reported in 220 oral glipizide 5mg to 6 healthy volunteers (Elvan patients (3.9%), necessitating treatment withdrawal der-Stahl et al. 1984), an effect possibly attribut in 103 patients (1.9%). A broadly similar incidence able to an inhibitory effect of indobufen on glipi of adverse effects has been reported in smaller zide metabolism. This finding implies that dosage studies of longer duration (Belcaro et al. I 990d; adjustment of glipizide may be necessary when co Rogan et al. 1990; SINBA Group, 1991). In these administered with indobufen. studies indobufen (200mg twice daily) was admin Indobufen did not influence the pharmacokin istered over a 12-month period and incidences of etic properties of the {3-adrenoreceptor antagonists adverse effects ranged between 3.2 and 9%. How propanolol 80mg or atenolol 100mg when each drug ever, one noncomparative multicentre study re was administered to separate groups of 6 volun ported a higher incidence of adverse effects (23%) teers (Elvander-Stahl et al. 1984). over a 2-year treatment period in 151 patients with 6. Dosage and·Administration occlusive vascular disease (Italian Multicentre Study Group 1985). The recommended daily dosage of indobufen is The most commonly reported adverse effects 100 to 200mg orally twice daily after meals. associated with indobufen were gastrointestinal, Dosage reduction to 100mg tWice daily in which accounted for approximately 80% of the total patients with mild to moderate renal impairment drug-related effects (Italian Multicentre Study (creatinine clearance 30 to 80 ml/min) and to Group 1985; fig. 5). These included dyspepsia (32% 100mg once daily in patients with moderate to sev of total reported effects), abdominal pain (21%), ere renal impairment (creatinine clearance < 30 ml/ constipation (9%), nausea and vomiting (10%). min) is recommended. Similar dose reductions are Haemostasis and coagulation disorders associated recommended for the elderly based on creatinine with indobufen therapy have been reported in a clearance rates. small number of patients (0.4%). Similarly low in 7. Place of Indohufen in Therapy cidences of skin and CNS disorders have been re ported (Lavezzari et al. 1989). Haemostatic ad Indobufen is a platelet aggregation inhibitor verse effects accounted for 8%, CNS effects 3% and which may be useful in the management of throm skin disorders 7% of total adverse effects. bosis. Studies have shown indobufen to be an ef- Indobufen: A Review 461 fective anti platelet agent which, unlike aspmn, be effective in decreasing the frequency and dur causes reversible inhibition of platelet cyclo-oxy ation of migraine attacks, suggesting that the drug genase, while having no apparent clinically signifi may have a beneficial effect on the prophylaxis of cant effects on any haemodynamic parameters. migraine, and further investigation is warranted. The majority of clinical studies to date have ex Indobufen may also be effective in the prevention amined the therapeutic efficacy of indobufen in of thrombus formation on haemodialysis mem patients with peripheral vascular disease and its branes, a major problem during haemodialysis prophylactic use in patients following revascular which results in decreased efficiency and increased isation surgery. blood loss. Placebo-controlled randomised studies have Aspirin is currently the most widely used anti found a significant and sustained increase in pain platelet drug; however, adverse effects are fre free and total walking distances following indob quently associated with its use. These effects are ufen therapy in patients with intermittent claudi mainly gastrointestinal and occur in approximately cation, and initial findings in a nonrandomised, 10 to 15% of patients receiving aspirin at dosages short term study suggest that indobufen has a more in excess of300 mg/day. Direct comparisons of the pronounced ameliorative action than aspirin in this tolerabilities of indobufen and aspirin have found setting; however, this observation remains to be a lower incidence of adverse effects and drug dis confirmed in well-controlled studies. In addition, continuation in patients receiving indobufen. It the relative efficacies of indobufen and ticlopidine should be noted that in these studies aspirin was in peripheral artery disease remain to be estab administered at high doses (975mg daily) and as lished. aspirin appears to be equally effective at lower doses The clinical significance of the apparent bene in the prevention and treatment of occlusive vas ficial effect of indobufen on microcirculatory para cular disease, a comparison of the incidences of meters found in studies in patients with peripheral gastrointestinal and haemorrhagic effects following vascular disease or diabetes has yet to be deter low dose aspirin (150 to 300mg daily) and indob mined. ufen is required before the relative tolerabilities of Indobufen 200mg twice daily appears to be sig the 2 compounds can be properly assessed. nificantly more effective than placebo in prevent Although indobufen has demonstrated compar ing vascular reocclusion following carotid endar able efficacy to aspirin in improving graft patency terectomyand femoropopliteal bypass surgery, and rates in patients following revascularisation sur at least as effective as aspirin 975mg daily in com gery, well-controlled, prospective studies are re bination with dipyridamole 225mg daily in im quired to compare the efficacy of the 2 drugs in proving coronary artery bypass graft patency. patients with intermittent claudication. In addition to its use in the treatment of inter Thus, initial studies have shown an improve mittent claudication and prevention of arterial graft ment in arterial graft patency associated with in occlusion, the efficacy of indobufen for secondary dobufen and have demonstrated a beneficial effect prevention of vascular events following myocard of the drug in patients with intermittent claudi ial infarction or transient ischaemic attack has been cation. Although these findings remain to be con investigated in a small number of controlled stud firmed in larger, well-controlled studies of longer ies. While these studies have indicated a potential duration, it would seem that indobufen offers po benefit of indobufen in reducing the incidence of tential benefits in the therapy and prophylaxis of secondary attacks over a 3-year period, further long occlusive vascular disease. Further, because of its term studies are required to confirm the prophy low incidence of gastrointestinal and haemorrhagic lactic efficacy of indobufen and its influence on effects, indobufen may represent a suitable altern patient prognosis. ative to high dose aspirin for long term use in this An initial study has found indobufen therapy to indication. 462 Drugs 44 (3) 1992 References corded in the morning in patients with ischaemic heart disease. Journal oflnternational Medical Research 17: 381-387, 1989 Crow MJ, Salter MCP, Donaldson DR, Rajah SM. Inhibition of Belcaro G. Vl,lsospasm in patients with intermittent claudication: platelet function with indobufen: correlation with plasma drug the role of indobufen. Current Therapeutic Research 47: 795- level. Thrombosis Research 38: 303-306, 1985 801, 1990a Curti T, Indobufen in the prevention of graft occlusion after fe Belcaro G. Vasospasm in intermittent claudication. Current moropopliteai bypass. Results of a multicentric double-blind Therapeutic Research 48: 667-675, 1990b study vs ASA + dipyridamole. XV World Congress of the Belcaro G, Pomante P, Barsotti A, De Simone P. Effects of in International Union of Angiology, Rome, 17 September, 1989 dobufen on the progression of diabetic microangiopathy. A mi Dalla Volta S, on behalf of SIAC (Studio Indobufene crocirculatory study using Laser-Doppler flowmetry. Current sull' Angioplastica Coronarica. Antiplatelet treatment in the Therapeutic Research 48: 451-459, 1990c prevention of restenosis after PTCA: An Italian Multicentre Belcaro G, Pierangeli A, De Simone P. Long-term evaluation of Study. Blood 74: 176A, 1989 the safety and efficacy of indobufen in cerebrovascular disease. Davi G, Francavilla G, Mattini A, Catalano I, Licata G, et al. Current Therapeutic Research 47: 444-451, 1990d Indobufen treatment in angina pectoris: effects on platelet Belcaro G, De Simone P. Long-term evaluation of indobufen in function and thromboxane synthesis. Current Therapeutic Re peripheral vascular disease. Angiology 42: 8-14, 1991 search 43: 1031-1037, 1988 Belcaro G, Errichi BM, De Simone P. Prevention of recurrent De Caterina R, Sicari R, Van A, Bernini W, Giannessi D, et al. deep venous thrombosis with indobufen. A 3-year follow-up The d-enantiomer form of indobufen totally accounts for the study using color duplex scanning. Angiology, in press, 1992. anti-cyclooxygenase and antiplatelet activity ex vivo and for Bielawiec M, Krupinski K, Bodzenta-Lukaszyk A, Plonowski A. the increase in bleeding time by indobufen in man. Throm On the effect of indobufen on platelet adhesion to subendoth bosis and Haemostasis 67: 258-263, 1992 elial matrix. Abstract 1373. Thrombosis and Haemostasis 56: Di Minno G, Silver MJ. Mouse antithrombotic assay: a simple 1077, 1991 method for the evaluation of antithrombotic agents in vivo. Buccianti G, Pogliani E, Miradoli R, Colombi MA, Valenti G, et Potentiation of antithrombotic activity by ethyl alcohol. Jour al. Reduction of plasma levels of betathromboglobulin and nal of Pharmacology and Experimental Therapeutics 225: 57- platelet factor 4 during haemodialysis: a possible role for a 60, 1983 short acting inhibitor of platelet aggregation. Clinical Nephrol Dodds AJ, Boyd MJ, Allen J, Bennet CP, Flute PT, et al. Changes ogy 18: 204-208, 1982 in red blood cell deformability and other haemorheological Campeau L, Erijalbert M, Lesperance J, Vaislic C, Grondin CM, variables following myocardial infarction. British Heart Jour et al. Atherosclerosis and late closure of aortocoronary sa nal44: 508-511, 1980 phenous vein grafts: sequential angiographic studies at 2 weeks, Donaldson DR, Salter MCP, Kester RC, Rajah SM, Hall TJ, et I year, 5 to 7 years and 10 to 12 years after surgery. Circulation al. The influence of platelet inhibition on the patency of fe 68: IIl-II7, 1983 moro-popliteal dacron bypass grafts. Vascular Surgery 4: 224- Carrieri P, Orefice G, La Pia S, Indaco A, D'Acunio F, et al. 230, 1985 Antiplatelet activity and tolerance of indobufen (K3920) in Edwards WH, Edwards Jr WH, Mulherin Jr JL, Jenkins JM. The cerebrovascular disease: a therapeutic approach. Pharmather role of antiplatelet drugs in carotid reconstructive surgery. An apeutica 3: 410-416, 1983 nals of Surgery 201: 765-770, 1985 Carrieri P, Orefice G. Study of platelet function in vitro and in Elvander-StAhl E, Melander A, Wahlin-Boll E. Indobufen inter vivo in patients. with transient cerebral ischaemia: effects of acts with the sulphonylurea, glipizide, but not with the II-ad short-term treatment with a new platelet antiaggregant drug, renergic receptor antagonists, propranolol and atenolol. British indobufen. Current Therapeutic Research 36: 681-686, 1984 Journal of Clinical Pharmacology 18: 773-778, 1984 Carrieri P, Donzelli R, Orefice G, Cerillo A, Volpentesta G, Tay Fornaro G, Rossi P, Mantica PG, Caccia ME, Aralda D, et al. ana G. Antithrombotic effect ofindobufen in fin experimental Indobufen in the prevention of thromboembolic events in model of arterio-arterial microanastomosis in the rat. Throm patients with cardiac disease. Circulation 82 (Suppl. 3): III- bosis Research 45: 195-199, 1987 602, 1990 Carrieri P, Orefice G, Sorge F. A double-blind placebo-controlled Fuecella LM, Corvi G, Moro E, Pogliani E, Tamassia V, et al. trial of indobufen in the prophylaxis of migraine. Acta Neu Pharmacokinetic, bioavailability and pharmacodynamic study rologica Scandinavica 77: 433-436, 1988 of indobufen (K 3920), an inhibitor of platelet aggregation after Cattaneo M, Bevilacqua C, Leechi A, Mannueci PM. In vitro and a single dose in man. European Journal of Clinical Pharma ex vivo effects of indobufen on human platelet aggregation, cology 15: 323-327, 1979 the release reaction and thromboxane B2 production. Haemo Fuster V, Chesebro JH. Aortocoronary artery vein graft disease. stasis 17: 293-300, 1987 Experimental and clinical approach for the understanding of Cerletti C, Manarini S, Colombo M, Tavani A. The (+)-enan the role of platelets and platelet inhibitors. Circulation 72 (Suppl. tiomer is responsible for the antiplatelet and anti-inflamma 5): 65-70, 1985 tory activity of (±)-indobufen. Journal of Pharmacy and Grasselli S, Guerciolini R, Iadevaia V, Parise P, Gresele P, et al. Pharmacology 42: 885-887, 1990 In vitro and ex vivo effects of indobufen on red blood cell Ciavarella N, Corvi G, Coviello M, Parato M, Pilolli D, et al. deformability. European Journal of Clinical Pharmacology 32: The effect of indobufen (K 3920) on platelet aggregation, plate 207-210, 1987 let factors 3~ 4 and some coagulation parameters in patients Green D, Santhanam S, Krumlovsky FB, Del Greco F. Elevated with venous thrombosis. Current Therapeutic Research 29: 503- II-thromboglobulin in patients with chronic renal failure: effect 508, 1981 ofhaemodialysis. Journal of Laboratory and Clinical Medicine Craveri A, Colombo L, Lanfredini M, Citella C, Picollo S, et al. 95: 679-685, 1980 Effect of indobufen on whole blood platelet aggregation re- Green RM, Roedersheimer R, DeWeese JA. Effects of aspirin and Indobufen: A Review 463 dipyridamole on expanded polytetrafluoroethylene graft pat Pogliani EM, Fantasia R, Perini C, Corvi G. Prevention of in ency. Surgery 92: 1016-1026, 1982 vivo platelet aggregation by indobufen in angina patients dur Grondin CM, Campeau L, Thornton JC, Engle JC, Cross FS, et ing exercise. Journal ofInternational Medical Research 9: 113- al. Coronary artery bypass grafting with saphenous vein. Cir 119, 1981b culation 79 (Suppl. I): 1-24-1-29, 1989 Pogliani EM, Colombi M, Cristoforetti G, Valenti G, Miradoli Hannington E. Migraine: a platelet disorder. Lancet 2: 720-723, R, et al. Beta-thromboglobulin and platelet factor 4 plasma 1981 levels during haemodialysis: effect of indobufen. Pharmath Italian Multicentre Study Group. Long-term antiplatelet activity erapeutica 3: 127-132, 1982 and safety of indobufen in patients with cardiovascular dis Pogliani EM, Fantasia R, Savino R, Montani M. Platelet release ease. International Journal of Clinical Pharmacology, Therapy reaction aM prostaglandin pathway activation in angina and Toxicology 23: 439-446, 1985 patients during exercise: effect of indobufen. Journal of Inter Lane IF, Irwin JTC, Jennings SA, Poskitt KR, Meek AC, et 'al. national Medical Research 11: 6-9, 1983 Effect of the cyclo-oxygenase inhibitor indobufen on platelet Pratesi C, Puli R, Milanesi G, Lavezzari M, Pamparana F, et al. accumulation in prosthetic vascular grafts. British Journal of Indobufen versus placebo in the prevention of restenosis 'after Surgery 73: 563-565, 1986 carotid endarterectomy: a double-blind pilot study. Journal of Lavezzari M, Milanesi G, Sacchetti G, Pamparana F. Indobufen: International Medical Research 19: 202-209, 1991 results of a postmarketing surveillance study on 5,642 cases. Rebuzzi AG, Natala A, Bianchi C, Mariello F, Coppola E, et al. Current Therapeutic Research 46: 19-27, 1989 Effects of indobufen on platelet thromboxane B2 production Limet R, David JL, Magotteaux P, Larock MP, Rido P. Preven in patients with myocardial infarction. European Journal of tion of aortocoronary bypass graft occlusion. Beneficial effect Oinical Pharmacology 39: 99-100, 1990' ofticlopidine on early and late patency rates. Journal of Thor Reid HL, Dormandy JA, Barnes AJ, Locke PJ, Dormandy TL. acic Cardiovascular Surgery 94: 773-783, 1987 Impaired red cell deform.ability in peripheral vascular disease. Mannucci L, Maderna P, Colli S, Lavezzari M, Sirtori CR, et al. Lancet 1: 666-667, 1976 Indobufen in a potent inhibitor of whole blood aggregation in Rodriguez R, Bono G, Lombardi B, Sacquegna T, DeDivitis E, patients with a high atherosclerotic risk. Thrombosis Research et al. Indobufen in the secondary prevention of stroke: The 48: 417-426, 1987 Italian multicentric study. XIV World Congress of Neurology, Moia M, Della Valle P, Castellana P, Cattaneo M, Mannucci PM. New Delhi, October 22-27, 1989 Indobufen inhibits thrombus formation and platelet adhesion Rogan J. Multicentre Ischaemic Attack Study Group. Indobufen to subendothelium both in vitro and ex vivo. 10th International in secondary prevention of transient ischaemic attack. Journal Conference on Thrombosis, Athens, 22 May, 1988 ofInternational Medical Research 18: 240-244, 1990 Nenci GG, Berrettini M, ladevaia V, Parise P, Ballatori E. In Salenius J-P, Haapanen A, Hruju E, Jokela H, Riekkinen H. Late hibition of spontaneous platelet aggregation and adhesion by carotid restenosis: aetiologic factors for recurrent carotid artery indobufen (K 3920). A randomized, double-blind crossover stenosis during long-term follow-up. European Journal of Vas study on platelet, coagulation and fibrinolysis function tests. cular Surgery 3: 271-277, 1989 Pharmatherapeutica 3: 188-194, 1982 Salter MCP, Mayor P, Crow MJ, Rajah SM, Davison AM. Mi Orefice G, Carrieri P, Indaco A, lorillo L, Fioretti A. A compar crothrombus formation on haemodialysis membranes: a pla ative study between indobufen and acetylsalicylic acid on {j cebo controlled randomized trial of two doses of indobufen. thromboglobulin, platelet factor 4 and platelet aggregation in Clinical Nephrology 24: 31-36, 1985 patients with transient ischemic attacks. Acta Neurologica 6: Sanita S. Blood filterability in cerebrovascular disorders with spe 97-102, 1984 cial reference to erythrocyte deformability. Stroke 126: 824- Ortega G, Gee W, Kaupp HA, McDonald KM. Postendarterec 828, 1981 tomy carotid occlusion. Surgery 90: 1093-1098, 1981 Savazzi GM, Castiglioni A, Cavatorta A. Effect of renal insuffi Pallone VM, Bentivoglio M, Corea L. Indobufen: a further ther ciency on the pharmacokinetics of indobufen. Current Ther apeutic measure for silent ischemic heart disease. Current apeutic Research 36: 119-125, 1984 Therapeutic Research 45: 407-413, 1989 Savazzi GM, Castiglioni A, Cavatorta A, Garini G, Montanari Patrignani P, Volpi D, Ferrario R, Romanzini L, De Somma M, M, et al. Effect of age on the pharmacokinetics of indobufen. et al. Effects of racemic, S- and R-indobufen on cyclooxygen International Journal of Clinical Pharmacology, Therapy and ase and lipoxygenase activities in human whole blood. Euro Toxicology 24: 265-269, 1986 pean Journal of Pharmacology 191: 83-88, 1990 Sheehan SJ, Monson JRT, Salter MCP, Rajah DS, Rajah SM, et Peters SHA, Jonker JJC, de Boer AC, den Ottolander GJH. The al. 1;he effect of indobufen on the thrombogenic potential of incidence of deep venous thrombosis in patients with an acute a dacron prosthesis in an artificial circulation. European Jour myocardial infarction treated with acenocoumarol or indob nal of Vascular Surgery 2: 223-227, 1988 ufen. Thrombosis and Haemostasis 48: 222-225, 1982 Signorini GP, Salmistraro G, Maraglino G. Efficacy of indobufen Pinto S, Abbate R, Favilla S, Panetta A, Gensini GF, et al. Ex in the treatment of intermittent claudication. Angiology 39: vivo and in vitro study of the effects of indobufen on endog 742-745, 1988 enous and exogenous arachidonic acid metabolism by plate SINBA Group. Indobufen versus aspirin plus dipyridamole after lets. Current Therapeutic Research 42: 243-252, 1987 coronary artery bypass surgery. Coronary Artery Disease 2: 897- Pogliani E, Buccianti G, Fantasia R, Valenti G. Beta-thrombog 906, 1991 lobulin and platelet factor 4 levels during haemodialysis. ESAO Steiner TJ, Joseph R, Clifford Rose F. Migraine is not a platelet Proceedings, October, Geneve, 1979. disorder. Headache 25: 434-440, 1985 Pogliani E, Corvi G, Mandelli V, Fuccella LM. Preliminary hu Stoney RJ, String ST. Recurrent carotid stenosis. Surgery 64: 705- man pharmacology studies on the inhibition of platelet aggre 710, 1976 gation by indobufen (K 3920). Haematologica 66: 159-170, Sumi M, Hagiwara M, Hidaka H. d-Indobufen inhibits colJagen 1981a induced intracellular calcium mobilization and inositol phos- 464 Drugs 44 (3) 1992 phates formation in human platelets. Thrombosis Research 59: Yinazzer H, Fuccella LM. Clinical pharmacology studies with in 319-326, 1990 dobufen (K 3920): inhibitor of platelet aggregation. Journal of Tamassia Y, Corvi G, Fuccella LM, Moro E, Tosolini G, et al. Clinical Pharmacology 20: 316-325, 1980 Indobufen (K 3920), a new inhibitor of platelet aggregation: Yisona A, Davanzo S, Bruno R, Pagnan A. Antiaggregant effect effect of food on bioavailability, pharmacokinetic andphar of indobufen (K3920) measured by the platelet aggregate fil macodynamic study during repeated oral administration to tration pressure test (PAFP). Journal of International Medical man. European Journal of Clinical Pharmacology 15: 329-333, Research II: 10-14, 1983 1979 Tremoli E, Maderna P, Sirtori M, Colli S, Corvi C, et al. Indob ufen treatment in type IIA hypercholesterolemia subjects: ef Correspondence: Lynda Wiseman, Adis International Limited. fects on platelet function and malondialdehyde production. 41 Centorian Drive, Private Bag 65901, Maitangi Bay, Auckland Pharmacological Research Communications 13: 847-859,1981 10, New Zealand. 本文献由“学霸图书馆-文献云下载”收集自网络，仅供学习交流使用。 学霸图书馆（www.xuebalib.com）是一个“整合众多图书馆数据库资源， 提供一站式文献检索和下载服务”的24 小时在线不限IP 图书馆。 图书馆致力于便利、促进学习与科研，提供最强文献下载服务。 图书馆导航： 图书馆首页 文献云下载 图书馆入口 外文数据库大全 疑难文献辅助工具