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Background: Indobufen is a drug that hinders the aggregation of platelets by reversibly repressing the cyclooxygenase enzyme, further bringing about diminished thromboxane production. During quality control of indobufen tablets, an unknown impurity was detected. Objective: To characterize an unknown impurity in indobufen tablets. Methods: A new method compatible with mass spectrometry detection was set up. A C18 column at 35 °C with a mobile phase consisting of aqueous buffer (including ammonium formate) and methanol (35: 65, v/v) was used at a flow rate of 1.0 mL/min at 228 nm. High-performance liquid chromatography quadrupole time-of-flight mass spectrometry mass spectrometry (HPLC-Q-TOF MS) was used to identify the impurity with the electrospray ionization (ESI) source in the positive ionization mode. Results: The results of HPLC-Q-TOF MS analysis indicated that the protonated molecule ions [M + H]+ of the unknown impurity was at m/z 312. Preparative LC method was put into practice with a Prep- C18 column with a mobile phase consisting of water and methanol (20: 80, v/v) at a flow rate of 20.0 mL/min at 228 nm. The assignment of the 1D and 2D NMR signals was performed for the unknown impurity. In addition, possible formation of the novel impurity was also studied. Conclusion: An unknown impurity in indobufen tablets was characterized. The impurity was assigned as 2-(4-(1-hydroxy-3-oxoisoindolin-2-yl) phenyl) butanoic acid.

This study aimed to investigate the pharmacodynamic effects of indobufen and low-dose aspirin in patients with coronary atherosclerosis. In the first phase, 218 patients with coronary atherosclerosis were randomly assigned to receive aspirin 100 mg once daily (standard dose); 100 mg once every 2 days; 100 mg once every 3 days; 50 mg twice daily; 75 mg once daily; 50 mg once daily; or indobufen 100 mg twice daily for 1 month. In the second phase, 20 healthy subjects were treated with indobufen 100 mg twice daily for 1 week followed after a 2-week washout by aspirin 100 mg once daily for 1 week. The primary outcome was arachidonic acid-induced platelet aggregation (PLAA), and the secondary outcomes included plasma thromboxane B2 (TXB2) and urinary 11-dehydro-TXB2 (11-dh-TXB2) levels at the end of each treatment. In the first phase, compared with aspirin 100 mg once daily: all aspirin groups had similar suppression of PLAA whereas indobufen group had significantly less suppressed PLAA. Aspirin given every second or third day, and indobufen produced less suppression of plasma TXB2. All treatment regimens produced similar inhibition of 11-dh-TXB2. In the second phase, compared with aspirin, indobufen produced less suppression of plasma TXB2 at 8 h and 12 h after the last dose. Aspirin 50 mg twice daily, 75 mg once daily, and aspirin 50 mg once daily produce antiplatelet effects that are similar to aspirin 100 mg once daily. Aspirin given less often than once daily and indobufen 100 mg twice daily do not suppress platelets as effectively as aspirin 100 mg once daily.

Increasing studies showed that several anti-platelet drugs turned out to be a promising strategy for inflammatory response. In this study, we investigated the protective efficiency of pretreatment of indobufen or aspirin combined with clopidogrel or ticagrelor (IACT) on cerebral ischemic injury via NF-κB/NLRP3 pathway. Ischemia/reperfusion (I/R) injury was simulated in vivo by middle cerebral artery occlusion/reperfusion (MCAO/R) model, and rats were pretreated with indobufen and aspirin and their combinations with clopidogrel or ticagrelor respectively. The platelet aggregation, cerebral infarct size, water content, neurological impairment and LDH release were measured. The relative expression of inflammasome mediated pyroptosis was determined by ELISA, RT-PCR, Tunel, Immunofluorescence and Western blotting as appropriate. In vitro, I/R injury was simulated in PC12 cells using oxygen glucose deprivation/reperfusion (OGD/R) and Lipopolysaccharide (LPS) to induce pyroptosis. The effect of combinations were significantly greater than MCAO/R group on decreasing the platelet aggregation, infarct size, brain edema, LDH release and neurologic impairment. LPS aggravated I/R-induced PC12 cell injury, which was significantly suppressed by pretreatment of IACT and Bay11-7082. Mechanistically, IACT alleviated transcriptionally encoded IL-1β, IL-18 and NLRP3 via inhibiting nuclear transportation of NF-κB. Importantly, at protein level, NLRP3, Caspase-1, IL-18, IL-1β and GSDMD were significantly decreased in combination groups both in vivo and vitro. IACT reduce inflammasome mediated pyroptosis in MCAO/R rats and OGD/R PC12 cells through inhibiting NF-κB/NLRP3 signaling pathway, which suggests that drug combination is a protective strategy with clinical potential against I/R-induced injury. Graphical abstract.

Isoindolinones are ubiquitous structural motifs in natural products and pharmaceuticals. Establishing an efficient method for structural modification of isoindolinones could significantly facilitate new drug development. Herein, we describe copper-promoted direct amidation of isoindolinone scaffolds mediated by sodium persulfate. The method exhibits mild reaction conditions and high site-selectivity, and enables the structural modification of the drug indobufen ester with various amides with yields of 49 to 98%. It is also gram-scalable. Additionally, the reaction mechanism appears to involve a radical and a carbocationic pathway.

BACKGROUND Worldwide, the treatment of patients with chronic kidney disease (CKD) remains a challenge as warfarin treatment can be associated with severe adverse events related to bleeding. Alternative anticoagulants that can be used in CKD remain to be identified. This study aimed to compare the effects of indobufen, a new antiplatelet agent, with warfarin in a rat model of adenine-induced CKD. MATERIAL AND METHODS Forty-eight male Wistar rats were treated with intragastric adenine to create the rat model of CKD and were divided into four groups: an untreated control group (N=12), a group treated with dimethyl sulfoxide (DMSO) (N=12), a group treated with indobufen, (N=12) and a group treated with warfarin (N-12). Treatment was given for 4 weeks and 8 weeks. Kidney histology was performed, and the degree of fibrosis was quantified using Masson trichrome staining. RESULTS In the rat model of adenine-induced CKD, Masson trichrome staining showed that the degree of kidney fibrosis in the indobufen group (26%) was significantly reduced (p

A method for the direct oxidation of various N-aryl tetrahydroisoquinolines and isoindolines to the corresponding lactams using α-angelica lactone as a catalyst was developed. The utility of the method was further demonstrated by synthesis of indoprofen and indobufen.

Background: Indobufen is a new generation of antiplatelet agents and has been shown to have antithrombotic effects in animal models. However, the efficacy of Indobufen on cerebral ischemia/reperfusion (I/R) injury and its mechanisms remain to be investigated. Methods: In this study, the efficacy of Indobufen with both pre- (5days) and post- (15days) treatment on rats suffering middle cerebral artery occlusion/reperfusion (MCAO/R, 2h of ischemia and 24h/15days of reperfusion) was investigated. Furthermore, human umbilical vein endothelial cells (HUVECs) were cultured and underwent oxygen glucose deprivation/reoxygenation (OGD/R) injury for in vitro studies. Relationship between Indobufen and pyroptosis associated NF-κB/Caspase-1/GSDMD pathway was preliminarily discussed.Results: The pharmacodynamic tests revealed that Indobufen ameliorated I/R injury by decreasing the platelet aggregation, infarct size, brain edema and neurologic impairment in rats and rescuing cell apoptosis/pyroptosis in HUVECs. The underlying mechanisms were probably related to pyroptosis suppression by platelet inhibition induced regulation of the NF-κB/Caspase-1/GSDMD pathway. Conclusion: Overall, these studies indicates that Indobufen exerts protective and therapeutic effects against I/R injury by pyroptosis suppression via downregulating NF-κB/Caspase-1/GSDMD pathway.

Indobufen is a new generation of anti-platelet aggregation drug, but studies were not sufficient on its anticoagulant effects. In the present study, the anticoagulant activity of indobufen was determined by monitoring the activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT) in rabbit plasma. We evaluated the anticoagulant mechanisms on the content of the platelet factor 3,4 (PF3,4), and the coagulation factor 1, 2, 5, 8, 10 (FI, II, V, VIII, X) in rabbits, as well as the in vivo bleeding time and clotting time in mice. The pharmacodynamic differences between indobufen and warfarin sodium, rivaroxaban, and dabigatran were further studied on thrombus formation and the content of FII and FX in rats. Animal experiments showed that intragastric-administrated indobufen can significantly reduce the APTT, PT, TT, PF3, FI, II, V, VIII, and X plasma contents. Its inhibitory effect on plasma FII was better than thrombin inhibitor dabigatran with effect on FX better than FXa inhibitor rivaroxaban. These results suggest that indobufen has some anticoagulant effects as strong as some conventional anticoagulants. The mechanism may be related to both exogenous and endogenous coagulation system.

The prescription of aspirin (acetylsalicylic acid (ASA)) to patients with a history of hypersensitivity to this drug could prove harmful. The aim of the study was to assess the antiplatelet activity and safety of a combined antiplatelet treatment with indobufen and clopidogrel in acute coronary syndrome (ACS) patients with hypersensitivity to aspirin, undergoing coronary stenting. Forty-two consecutive ACS patients treated with stent implantation were randomly assigned to receive clopidogrel 75 mg daily (loading dose 300 mg) plus indobufen 100 mg twice a day (group A), or clopidogrel 75 mg daily, after 300 mg of loading dose (group B). Platelet activity and safety were monitored in both groups at 1, 3, 6, 12, and 18 months with laboratory and clinical evaluation. A lower value of max % platelet aggregation to arachidonic acid and collagen was found in group A compared to group B (31.79 ± 27.33 vs. 73.67 ± 19.92; p 0.0001 and 28.53 ± 21.32 vs. 73.58 ± 17.71; p 0.0001, respectively). There was no difference in max % of platelet inhibition to adenosine diphosphate between the two groups (14.23 ± 18.92 vs. 10.30 ± 18.97; p = 0.23). In the population that was under indobufen treatment, the serum thromboxane B2 (TXB2) production at 1 week and 1 month was very low (2.6 ± 1.6 ng/ml and 3.0 ± 2.7 ng/ml, respectively; p = 0.82). The combined treatment was well tolerated in group A patients. This study suggests that the combined antiplatelet treatment with clopidogrel and indobufen could be a good option in ACS patients with hypersensitivity to aspirin undergoing coronary stenting.

Background— The most suitable approach for patients with aspirin hypersensitivity undergoing percutaneous coronary intervention remains to be assessed. Methods and Results— Pubmed, Google Scholar, and Cochrane were systematically searched for papers describing protocols about aspirin hypersensitivity in the percutaneous coronary intervention setting. Discharge from hospital with aspirin was the primary end point, whereas rates of adverse reactions being a secondary outcome. An online international survey was performed to critically analyze rates of aspirin hypersensitivity and its medical and interventional management. Eleven studies with 283 patients were included. An endovenous desensitization protocol was performed on one of them, with high efficacy rate (98%) and a low adverse reaction rate when compared with oral administration. No significant differences were reported among the oral protocols in terms of efficacy (less versus more fractionated [95.8% {95.4%–96.2%} versus 95.9% {95.2–96.5%}]), whereas higher incidence of rash and angioedema were reported for protocols with Conclusions— Available protocols for aspirin hypersensitivity are effective and safe, representing a feasible approach for patients needing dual antiplatelet therapy.

A stereospecific CE method was elaborated for the quantification of ibuprofen enantiomers and their major phase I metabolites: 2'-hydroxy-ibuprofen and 2'-carboxy-ibuprofen in plasma and urine. Optimal temperature and pH of BGE were established to obtain complete separation of eight ibuprofen chiral compounds and (+)-S indobufen, applied as an internal standard, during one analytical run. After isolation from biological matrices using SPE on an octadecyl stationary phase, the analytes were separated and resolved up to 10 min in a silica capillary filled with BGE, consisting of heptakis 2,3,6-tri-O-methyl-beta-CD in triethanolamine-phosphate buffer, pH 5.0. Complete enantioseparation of the all analytes confirmed specificity of the method. The calibration curves were linear in the range of 0.1-25.0 mg/L for IBP enantiomers and their chiral metabolites in 0.5 mL of plasma and 1.0-200.0 mg/L in 0.05 mL of urine. Following SPE procedure, recovery of the chiral analytes from the two media was in the ranges of 82-87%, 90-95% and 70-76% for ibuprofen, 2'-hydroxy-ibuprofen and 2'-carboxy-ibuprofen enantiomers, respectively. The validated method was successfully applied in pharmacokinetic investigations of IBP enantiomers as well as free chiral metabolites in reference to the genetic polymorphism of CYP450 2C isoenzymes.

Non steroid anti-inflammatory drugs (NSAIDs) are largely used for treatment of acute and chronic pain, even for long periods of time (months or years). While it is known that their use is frequently associated with gastrointestinal damage, including major bleedings from peptic ulcer, the risk of cardiovascular events related to NSAID has received much less attention. However, there is a large body of evidence showing that NSAIDs (both “traditional”, such as diclofenac or indobufen, and selective cyclooxygenase inhibitors, COX-2) are associated with a significant increase of risk of cardiovascular events, both fatal and nonfatal. Consequently, several options have been proposed for the treatment of pain, including the use of analgesic drugs with different mechanisms of action, such as the opiates. Of interest, the Italian Drug Agency (AIFA) published a few years ago a warning (Nota 66) on the careful prescription of NSAIDs in patients with overt heart disease, such as coronary artery disease and heart failure. Aim of this paper is to present the current status of knowledge on the proper use of NSAIDs and other analgesic drugs in the management of acute and chronic pain.

The aim of this study is to quantify the extent and recovery of platelet inhibition after administration of indobufen and aspirin in healthy volunteers. Indobufen inhibits platelet aggregation by reversibly inhibiting the platelet cyclooxygenase enzyme, thereby suppressing thromboxane synthesis. Twenty healthy volunteers completed the study and received aspirin (200 mg/day for 2 weeks) followed by a 4-week washout period and then indobufen (200 mg twice a day for 2 weeks). The percent (%) inhibition of platelet aggregation (IPA) was assessed using arachidonic acid (0.5 mg/ml) and adenosine diphosphate (5 µM) at 4, 12, 24 and 48 hours after last dose of each drug. IPA assessed using arachidonic acid as the agonist was similar at 4 hours after the last dose of indobufen (81.07 ± 9.36%) and aspirin (96.99 ± 0.29%, p = 0.10), but significantly lower at 12 hours (74.04 ± 9.55% vs. 97.94 ± 0.28%, p = 0.02), 24 hours (33.39 ± 11.13% vs. 97.48 ± 0.32%, p < 0.001) and 48 hours (14.12 ± 9.74% vs. 98.22 ± 0.31%, p < 0.001) after indobufen, compared to the relative values for aspirin. IPA assessed using adenosine diphosphate as the agonist was similar in the two groups at 4, 12 and 24 hours after the last dose, but significantly lower 48 hours after the last dose of indobufen, compared to the relative value for aspirin (1.98 ± 3.57% vs. 12.61 ± 2.71%, p = 0.002). Indobufen (200 mg twice a day) caused equivalent initial inhibition of platelet aggregation to aspirin (200 mg daily), and the anti-aggregation effect diminished faster than after aspirin.

Summary Background The risk of major upper gastrointestinal bleeding associated with various antiplatelet drugs and the protection conferred by gastroprotective agents are not well defined. Aim To estimate the risk of upper gastrointestinal bleeding associated with the use of antiplatelet drugs and its prevention by gastroprotective agents. Methods In a case-control study, we compared all cases of upper gastrointestinal bleeding from a gastric or duodenal lesion in patients over 18 years of age (2813 cases), with 7193 matched controls. Odds ratios of upper gastrointestinal bleeding for individual antiplatelet drugs with adjustment for potential confounders were estimated. Results The individual risks of upper gastrointestinal bleeding were cardiovascular acetylsalicylic acid 4.0 (3.2–4.9), clopidogrel 2.3 (0.9–6.0), dipyridamole 0.9 (0.4–2.0), indobufen 3.8 (1.2–12.2), ticlopidine 3.1 (1.8–5.1) and triflusal 1.6 (0.9–2.7). Concomitant proton pump inhibitors decreased all risk estimates. For acetylsalicylic acid plus a proton pump inhibitor, the odds ratio was 1.1 (0.5–2.6). As a group, antiplatelet drugs accounted for 14.5% of all cases of upper gastrointestinal bleeding, i.e. 58 per million per year (334 per million per year among those older than 70 years). Conclusions The risk of upper gastrointestinal bleeding is substantially decreased by the concomitant use of proton pump inhibitors. The risk of acetylsalicylic acid plus a proton pump inhibitor seems lower than that of ticlopidine or clopidogrel.

Indobufen (Ibustrin®), a reversible inhibitor of platelet aggregation, exists in two enantiomeric forms in 1:1 ratio. Here, we characterized the anti-platelet effect of S- and R-indobufen using response surface modeling using NONMEM® and predicted the therapeutic doses exerting the maximal efficacy of each enantioselective S- and R-indobufen formulation. S- and R-indobufen were added individually or together to 24 plasma samples from drug-naive healthy subjects, generating 892 samples containing randomly selected concentrations of the drugs of 0-128 mg/L. Collagen-induced platelet aggregation in platelet-rich plasma was determined using a Chrono-log Lumi-Aggregometer. Inhibitory sigmoid Imax model adequately described the anti-platelet effect. The S-form was more potent, whereas the R-form showed less inter-individual variation. No significant interaction was observed between the two enantiomers. The anti-platelet effect of multiple treatments with 200 mg indobufen twice daily doses was predicted in the simulation study, and the effect of S- or R-indobufen alone at various doses was predicted to define optimal dosing regimen for each enantiomer. Simulation study predicted that 200 mg twice daily administration of S-indobufen alone will produce more treatment effect than S-and R-mixture formulation. S-indobufen produced treatment effect at lower concentration than R-indobufen. However, inter-individual variation of the pharmacodynamic response was smaller in R-indobufen. The present study suggests the optimal doses of R-and S-enantioselective indobufen formulations in terms of treatment efficacy for patients with thromboembolic problems. The proposed methodology in this study can be applied to the develop novel enantio-selective drugs more efficiently.

Steady-state pharmacokinetics of indobufen (INDB) enantiomers administered as racemic INDB (rac-INDB) tablets and bleeding time were studied in patients. Two-hundred mg INDB tablets (Ibustrin) were administered twice daily for 7 days to obliterative atherosclerosis patients. Enantiospecific reversed phase (RP) HPLC with UV detection (lambda = 275 nm) was used for determination of INDB enantiomers in serum of patients. The ratio AUCR:AUCS equalled 1.7 +/- 0.2 as a result of higher (-)-R-enantiomer serum levels. The (+)-S-enantiomer was more rapidly eliminated (oral clearance, Cl = 1.1 +/- 0.3 L/h) than its (-)-R-antipode (Cl = 0.7 +/- 0.2 L/h). Therefore, the mean steady/state levels of (-)/R/enantiomer (13.5 +/- 3.8 mg/L) exceeded those of its (+)-S-enantiomer (7.8 +/- 1.8 mg/L). Furthermore, half-life (t1/2) was significantly shorter for (+)-S-INDB (t1/2 = 4.5 +/- 1.2 h as compared to (-)-R-INDB (t1/2 = 7.4 +/- 2.4 h). However, no significant differences were observed in the respective Vd values. The bleeding time of patients was not significantly extended. The above pharmacokinetic data provide a rationale for potential future replacement of INDB racemic tablets with tablets of its (+)-S-enantiomer.

The influence of administration route (oral or intramuscular (i.m.)) on the pharmacokinetics of total indobufen (INDB) enantiomers was studied in healthy volunteers after a 200 mg dose as a single oral tablet or i.m. injection. Enantiospecific reversed phase (RP) HPLC with UV detection was used for the determination of INDB enantiomers in serum. INDB enantiomers were isolated from serum by solid phase extraction (SPE) procedure using C(18) columns. INDB enantiomers were converted to their L-leucinamide diastereoisomers and separated on a C(18) HPLC column. INDB from i.m. injections is absorbed faster (t(max) = 0.6-0.9 h) than from tablets (t(max) = 1.3-1.8 h). The area under curve (AUC) after administration of the tablet was slightly higher than after i.m. injection. The pharmacokinetic behaviour of (+)-S- and (-)-R-INDB after administration of the tablet was different from i.m. injection of racemic INDB. The (+)-S-enantiomer is more rapidly eliminated than its (-)-R-antipode. Statistically significant differences also occurred between enantiomers in AUC, first order elimination rate constant (k), clearance (Cl). The ratio AUC(R):AUC(S) was similar for the tablet (1.57-1.62) and i.m. injection (1.59-1.62). It was concluded that the formulation and extent of ionisation of rac-INDB (acid or sodium salt of INDB) do not significantly influence its stereoselective pharmacokinetics.

Seventy-one patients with peripheral arterial occlusive disease (PAOD) were random ized into two groups of different treatment modalities. The diagnosis of PAOD was estab lished by history of intermittent claudication, clinical examination, and by Doppler pressure assessment or lower extremity arteriography. After a three-month washout period, 35 patients (Group 1) started treatment with indobufen (400 mg per day) and 36 patients (Group 2) with pentoxifylline (600 mg per day). Twenty-nine patients from each group completed six months of treatment. Both of the drugs significantly improved maximal and pain-free walking distances, but the effect of indobufen was more pronounced than that of pentoxifylline. Patients with PAOD exhibited signs of hyperco agulation. Fibrinogen, D-dimer, and b-thromboglobulin concentrations did not change significantly following treatment in both of the groups. The authors observed a decrease of platelet aggregation after treatment with indobufen and a decrease of F1+2 fragment and PAI-1 antigen after treatment with pentoxifylline.

The anaesthesiologist plays a central role in co-ordinating the combined application of the various blood saving techniques. In fact, to carry out transfusion therapy correctly, the anaesthesiologist must plan the right number of units of predeposit blood during the first examination, estimate the salvage of intra and post operative blood loss and spread the infusion of the units over the first three days in order to keep the patient in a state of haemodilution. From January 1992 to June 1994 in the department of anaesthesia and the intensive care unit, 980 patients were treated for total joint replacement: 714 total hips (7 after removal of plates and screws) 145 revisions, and 121 total knee prostheses. Basal Hb was 13.4 ± 1.4 g/dl (range 6.7 – 17.9 g/dl). Homologous transfusions were carried out in 6.3% of these patients. The need to use homologous transfusions was negatively influenced by female sex, coronary heart disease (p = 0.005), length of surgery and type of antithromboembolic prophylaxis (indobufen has a significantly low incidence - p = 0.0001 - compared to calcium heparin or low molecular weight heparin).

To assess the causes of failure in a blood saving program and the consequent need for homologous transfusions during major orthopedic surgery, data were collected from six orthopedic centers where an autotransfusion program was carried out from 1992–1994. The 1,576 (1,016 female and 560 male) patients studied (average age 63.6 ± 10 years) were treated either for total hip prosthesis (1,144 pts) total knee prosthesis (212 pts), plate and screw removal plus hip prosthesis (8 pts), hip revision (cup 48 pts, stem 10 pts, cup plus stem 146 pts) and total knee revision (8 pts). Ninety percent of patients did not undergo homologous transfusions, which was significantly connected to: male sex (8% versus 11.7% p=0.02), younger age (63.2 vs 66.9 years, p=0.0001), higher weight (male 76 vs 70.7 Kg. p = 0.003, female 65.6 vs 61.9 Kg. p = 0.0003); higher baseline Hb (13.9 vs 12.8 gl dl, p = 0.0041), shorter operation time (110 vs 128 minutes, p = 0.0001); use of indobufen for antithromboembolic prophylaxis (indobufen 4.6% vs heparin calcium 15.2% vs low molecular weight heparin 9% p = 0.0001). On the contrary, the factors favoring homologous transfusions were: peripheral anesthesia (spinal and epidural 15.3% vs general 9.3% vs integrated 9.8% p = 0.016), total hip or knee revision, fixation device removal before hip prosthesis, systemic hypertension and coronary heart disease.

The binary phase diagram of the enantiomers of indobufen, 1 (Ibustrin), an antithrombotic drug, has been investigated by differential scanning calorimetry (DSC); 1 is a racemic compound (racemate) with melting point lower than that of the enantiomers. Its thermal behaviour (DSC) has been examined and is discussed in comparison with other physical methods (IR spectroscopy and X-ray powder diffraction). Absolute configuration has been assigned to the enantiomers by 1H-NMR correlations. © 1995 Wiley-Liss, Inc.

Recently, it has been established that aspirin significantly reduces the risk of vascular events such as stroke, myocardial infarction and vascular death.[1] The aim of this study was to examine the ex vivo effects of d-indobufen on platelet aggregation and thromboxane A2 (TXA2) production in patients with cerebrovascular disease with a view to its potential as an alternative to aspirin in the prevention of cerebrovascular events.

Oral administration of indobufen to male rats for three days at daily doses of 5, 10 and 20 mg kg−1 resulted in no changes in liver total glutathione, cytosolic glutathione S-transferases or microsomal epoxide hydrolase. Reduced glutathione appeared slightly diminished to about 84% of control at the highest dose level. Microsomal cytochrome P450-dependent ethoxyresorufin O-de-ethylase and pentoxyresorufin de-alkylase activities were decreased to 64% (not significantly) and 67% of control at the lowest dose level. 6α- and 7α-Hydroxytestosterone activities were decreased to 67 and 68% of control at the highest dose level. Cyanide-insensitive peroxisomal fatty acid β-oxidation was increased to 223, 261 and 232% of control at doses of 5, 10, and 20 mg kg−1, respectively. The results obtained in this study are indicative of the action of indobufen as a weak peroxisome proliferator in male rat liver, and suggest a slight but toxicologically insignificant inhibitory action of this drug on microsomal cytochrome P450-dependent enzyme activities.

Saphenous vein coronary artery bypass graft patency can be increased by antiplatelet therapy. Aspirin plus dipyridamole are effective but are associated with tolerability problems. Indobufen is a possible alternative antiplatelet agent that may be better tolerated. A prospective, randomized, double-blind, parallel-group study was undertaken to compare the efficacy and safety of indobufen 200 mg twice daily with aspirin 300 mg thrice daily plus dipyridamole 75 mg thrice daily in preventing occlusion of autologous saphenous vein coronary artery bypass grafts. A total of 803 patients were randomized in the study, of whom 552 had a follow-up coronary angiogram approximately 1 year after operation. All anastomoses were patent in 56 % of indobufen-treated patients and 59 % of aspirin-dipyridamole recipients (p = 0.384). The percentage of all anastomoses patent was 82 % in the indobufen group and 83 % in the aspirin-dipyridamole group (p = 0.297). Mean postoperative blood loss was significantly less in the indobufen group (p = 0.043). Patients who received indobufen also had significantly fewer adverse events considered to be treatment-related compared with aspirin-dipyridamole recipients (p = 0.02). At the doses tested indobufen was as effective as aspirin plus dipyridamole in preventing occlusion of saphenous vein grafts and was better tolerated. Because indobufen was associated with less postoperative blood loss it may be used before operation in coronary artery bypass grafting.

Pellets containing Indobufen as model drug were prepared by using the centrifugal-rotary fluidized bed equipment without employing non-pareil seeds.The influence of different amounts of spheronization enhancer (microcrystalline cellulose) and of different fillers (lactose, mannitol, calcium carbonate) on both processing and physical properties of the pellets were evaluated.The preparation reproducibility was also investigated. The use of 30% w/w of microcrystalline cellulose was essential to produce a good quality pellets; the incorporation of filler decreased the qualitative characteristics of the pellets.The water feeding rate proved to be an important parameter for the pellet growth.Therefore, the results showed that this technology based on the rotary fluidized bed is a promising and alternative method in producing pellets.

Background Dual antiplatelet therapy (DAT, i.e. aspirin+thienopyridine) has been shown to reduce the risk of stent thrombosis (ST) and myocardial infarction (MI) after coronary stent implantation. Data regarding alternative antiplatelet therapy in patients with allergy or intolerance to aspirin are lacking. Methods This study is a retrospective analysis of consecutive patients with adverse reactions to aspirin who received an alternative combination of DAT (indobufen, trapidil, or triflusal in association with a thienopyridine) after elective implantation of either drug-eluting (DES) or bare-metal stents (BMS). Endpoints analyzed were cardiac death, MI, ST and bleeding. Results A total of 127 patients undergoing stenting of 267 lesions (DES 84%, BMS 16%), were identified between June'99 and November'08. Reasons for not taking aspirin included gastrointestinal intolerance (53.5%), allergy (39.4%), non-gastrointestinal bleeding (5.5%) and others (1.6%). Aspirin was substituted with indobufen (64.6%), trapidil (26.8%), triflusal (6.3%), or a combination of indobufen+trapidil (2.4%). Median duration of DAT was 369days [IQR 273–1053] after DES and 46.5days [IQR 30–699] after BMS implantation. Only 3.1% of patients prematurely discontinued DAT. During a median follow-up of 1161days [IQR 781–1538], rates of cardiac death and MI were 3.1% and minor bleeding occurred in 1.5%. There was 1 very late definite ST occurring 2days after DAT discontinuation and no probable ST. Conclusions In this cohort of patients with aspirin intolerance undergoing coronary stent implantation, the combination of a thienopyridine with indobufen, trapidil, or triflusal was associated with a low rate of cardiac death, ST and MI.

The excretion balance and urinary metabolites of the S-enantiomer of indobufen, ((S)2-[p-(1-oxo-2-isoindolinyl)-phenyl]butyric acid), a platelet aggregation inhibitor, were studied in rats and mice after oral administration. The urinary metabolic profile exhibited a marked species difference. The major metabolic pathway in the mouse was acyl glucuronidation followed by renal excretion, whereas in rat urine 5-hydroxylation and subsequent sulphation at the introduced hydroxyl group accounted for almost all recovered radioactivity. Indobufen glucuronide was the major biliary metabolite in the rat, while very little indobufen glucuronide was present in the urine of intact or bile duct-cannulated rats. A marked dose-effect on the elimination and metabolism of S-indobufen was demonstrated in the rat. The recovery (% dose) of 5-hydroxyindobufen and its sulphate after the lower dose of the enantiomer (10 mg/kg) was some 2.8-fold higher compared with the higher dose of 20 mg/kg.

A multiple units dosage form has been prepared in order to control the release of d-Indobufen, a carboxylic acid used as an inhibitor of platelet aggregation.The system consists of cores containing the active substance coated with a diffusive film and represents a classic “reservoir” system.Extrusion-spheronization was used in order to prepare the active cores. The drug release control was obtained by modifying both the core composition and the film composition characteristics.Acid and basic compounds were incorporated in the core to influence the inside microenvironment pH. Polymers chosen for the film formulation were: ethylcellulose (Aquacoat) and copolymers of acrylic esters with differing permeability characteristics (Eudragit RL/RS 30D).Technological and physical characteristics of coated pellets proved the production feasibility of an extended release multiple unit dosage form of d-Indobufen.Preliminary data of accelerated stability indicated the important role played by the thermal treatme...

We have studied in a homologous system the effect on different platelet functions of cells isolated from 26 human tumor tissues (11 breast carcinomas, 11 colon carcinomas, 2 pancreatic carcinomas, 1 gastric carcinoma and 1 esophageal carcinoma). Tumor cells (10(5)/ml) significantly increased platelet adhesion to glass beads; they were also found to possess a potent platelet aggregating activity and aggregation was accompanied by significant release of ATP and platelet derived growth factor (PDGF) and by production of TXB(2). Preincubation of platelets with a low concentration (1 µM) of indobufen, a cyclooxygenase inhibitor, significantly reduced tumor cell induced TXB(2) production and ATP release, while the other platelet functions were not modified. Higher concentrations of the drug (10 or 100 µM) were also able to inhibit tumor cell-induced platelet aggregation and PDGF release, while platelet adhesion to glass beads was unchanged even at these doses. Finally, preincubation of neoplastic cells with indobufen (400µM) had no effect on their ability to induce platelet aggregation, TXB(2) production and ATP release. These data demonstrate that cyclooxygenase blockade in platelets has different effects on several platelet functions activated by the tumor cells that were investigated.

The synthesis of some 2(4)-imidazol-1-yl-4(2)-cycloalkylaminopyrimidines are reported. The compounds demonstrated a marked antiaggregating activity superior to dipyridamole, ASA, ticlopidine and similar to that of indobufen.

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.

The synthesis of some 2(4)-imidazol-1-yl-4(2)-cycloalkylaminopyrimidines are reported. The compounds demonstrated a marked antiaggregating activity superior to dipyridamole, ASA, ticlopidine and similar to that of indobufen.

The inhibitory effect of 50 mg/kg lysyl acetylsalicylic acid (ASA) intravenously injected 24 and 4 h before 80 μg/kg adrenaline, 40 mg/kg indobufen injected 15 min before, or a combination of ASA plus indobufen on the platelet aggregation and kinetics was evaluated in anaesthetized dogs previously injected with 111indium- (111In-) labelled platelets using γ-camera dynamics studies. The highest degree of inhibition, indicated by the lowest platelet aggregation ratio decrease and the most significant 111In-labelled platelet mobilization from hepatic and splenic stores with a corresponding increase of labelled and unlabelled platelet counts in blood, was obtained in ASA-treated dogs. Such changes were less marked when ASA plus indobufen was injected. In indobufen-treated dogs a similar mobilization of 111In-labelled platelets with an increase in circulating platelet numbers was evident only after the second adrenaline injection. It is concluded that platelet mobilization is mainly dependent on the production of an ASA-sensitive substance.

Racemic indobufen inhibits human platelet aggregation by reducing thromboxane (TX) A2 biosynthesis. In order to ascertain which of the two optical isomers is responsible for its pharmacological activity, we compared the effects of racemic (SR +/-), S(+) enantiomer and R(-) enantiomer indobufen on cyclooxygenase and 5-lipoxygenase activities by assessing the biosynthesis of TXB2, prostaglandin (PG) E2 and leukotriene (LT) B4 in human whole blood stimulated with the Ca2+ ionophore A23187. Racemic indobufen caused a dose-dependent inhibition of TXB2 and PGE2 production (IC50: 0.53 +/- 0.06 and 0.34 +/- 0.02 micrograms/ml, respectively; mean +/- S.D., n = 4). S-Indobufen was approximately 2-fold more potent than the racemate in inhibiting the synthesis of cyclooxygenase products. R-Indobufen affected the same enzyme but only at considerably higher concentrations (IC50: 53 +/- 8 micrograms/ml, n = 3). Serum LTB4 concentrations were significantly reduced only at indobufen concentrations greater than 50 micrograms/ml. In conclusion, indobufen is a selective inhibitor of the cyclooxygenase activity of platelet PGG/H synthase in a concentration range corresponding to the therapeutic plasma levels in man. This inhibitory effect is largely due to the S isomer of the drug.

The plasma pharmacokinetics and urinary elimination of the enantiomers of indobufen, a novel platelet aggregation inhibitor, have been studied in rats and mice given either the racemic compound or the individual enantiomers (rat 8 mg/kg racemate, 4 mg/kg enantiomers; mouse 25 mg/kg racemate, 12.5 mg/kg enantiomers). Enantiospecific analysis of indobufen in plasma and urine was achieved by HPLC of its L-leucinamide diastereoisomers. In rat, the two enantiomers have very different plasma elimination half lives (S, 3.9 hr; R, 12.2 hr), irrespective of the optical form administered. The plasma concentration-time curves of S-indobufen were identical after racemic or S-indobufen, but the plasma levels of R-indobufen were lower after the R-enantiomer than after the racemate. Urinary recovery of free and conjugated indobufen was less than 3% of the dose, independent of the optical form administered. In the mouse, R-indobufen was cleared from plasma more rapidly than its S-antipode (elimination T1/2 R, 2.5 hr; S, 3.8 hr) but differences were smaller than those seen in the rat. The plasma concentration-time curves of the S-enantiomer were the same after racemic or S-indobufen, but levels of its R-antipode were much lower when it was given alone than after administration of the racemate. The urinary recovery of free and conjugated indobufen also exhibited enantioselectivity, with preferential elimination of the S-enantiomer.

We obtained evidence that the cyclooxygenase inhibitor d-indobufen, (+)2[p-(1-oxo-2-isoindolinyl)phenyl] buthylic acid has a potent and specific inhibitory effect on collagen-induced aggregation and 40K-protein phosphorylation (Mamiya, S., Hagiwara, M., Ishikawa, T., and Hidaka, H. Thromb. Res. 54, 447, 1989) (1). In Fura-2 loaded platelets, d-indobufen inhibited collagen-induced intracellular calcium mobilization in a dose dependent manner and this inhibitory effect on calcium mobilization paralleled that on aggregation, either in the presence or absence of extracellular free calcium ions. This compound inhibited inositol phosphates (IPs) formation in collagen-stimulated platelets. In arachidonic acid-stimulated platelets, d-indobufen caused a lag on calcium mobilization, as observed with arachidonic acid-induced aggregation. There was no significant effect on thrombin- or A23187-induced calcium mobilization or on aggregation. These observations suggest that the collagen receptor couples to a distinct intracellular calcium mobilization system possibly via inositol phospholipid metabolism and that d-indobufen blocks the collagen-induced aggregation by arresting mobilization of intracellular calcium.

The secondary prevention of transient ischaemic attacks was assessed in 270 patients treated orally with 100 mg indobufen given twice daily for 12 months. After 1 month's treatment, the average number and average incidence of transient ischaemic attacks were reduced significantly ( P < 0.001) and remained suppressed throughout the treatment period. Treatment was interrupted in 17 patients: in two because of side-effects (gastric disturbances); in 10 because of fatal events (six completed strokes, two myocardial infarcts and two unrelated deaths); and in five due to poor protocol compliance. Progression to reversible ischaemic neurological deficit occurred in five patients. Most side-effects were mild and transient, mainly occurring in the first month of treatment. Overall, indobufen was judged to have good efficacy and safety by both patients and physicians.

This study was designed to evaluate whether indobufen and ticlopidine can induce changes in the size of left ventricular thrombi and variations in the deposition of platelets on thrombus surface. Forty-seven patients with left ventricular thrombosis, who were not treated with antithrombotic drugs, were prospectively evaluated with 111In-oxine platelet imaging and two-dimensional echocardiography. The first scintigraphic examination was negative in 15 of the 47 patients with left ventricular thrombosis, thus they were excluded from further evaluation. The remaining 32 patients with evidence of labeled platelet deposition on the thrombus were divided into three groups. Group 1 comprises 11 patients treated with different doses of ticlopidine: 6 with 250 mg/day, and 5 with 500 mg/day. Group 2 comprises 12 patients who received 400 mg/day of indobufen. Group 3 comprises 9 patients who were not treated with antithrombotic drugs. All 32 patients underwent repeated 111In-oxine platelet imaging and echocardiography 40 +/- 11 days after the first examination. During treatment with ticlopidine, deposition of labeled platelets on the thrombus became absent in 2 patients (500 mg/day), and reduced in 5 (2 treated with 250 and 3 with 500 mg/day). A decrease of platelet deposition on the thrombus was also observed in 5 of the 12 patients receiving indobufen and in only 1 of 9 controls. With regard to thrombus dimensions, 1 patient treated with ticlopidine showed a decrease in thrombus size associated with a reduction of the scintigraphic activity. In conclusion, a decrease of the platelet uptake on the thrombus surface, without significant changes in the size, was detected in most patients during treatment with indobufen and ticlopidine.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: To assess whether indobufen, a reversible inhibitor of platelet cyclooxygenase (Cox) activity, affects tissue factor (TF) in human monocytes and to investigate the relationship between Cox-derived products and TF. Methods: TF was evaluated in isolated adherent monocytes, both resting and lipopolysaccharide (LPS)-stimulated, in terms of procoagulant activity, protein, and mRNA levels. The expression of TF surface antigen was determined in LPS-stimulated whole blood monocytes by flow cytometry. The levels of the stable thromboxane A2 (TxA2) metabolite, TxB2, and of prostaglandin E2 (PGE2) were measured in monocyte supernatant by immunoenzymatic techniques. Cox-1 and Cox-2 protein level, tyrosine phosphorylation, and mitogen-activated protein kinase (MAP-kinase) activation were determined by Western blot analysis. Results: Indobufen prevents TF expression and activity both in isolated and in whole blood monocytes. Reduction of TxA2 synthesis, coupled with a lack of effect on PGE2 levels and prevention of ERK1/2 phosphorylation are highlighted as the mechanisms through which indobufen negatively affects TF. Conclusions: Data show that indobufen down-regulates TF in monocytes. This novel activity, coupled with the antiplatelet effect of the drug, may add benefit for its use in the management of atherothrombosis.

Background People with nonrheumatic atrial fibrillation (NRAF) who have had a transient ischemic attack (TIA) or minor ischemic stroke are at risk of recurrent stroke. Both warfarin and aspirin have been shown to reduce the recurrence of vascular events. Objectives The objective of this review was to compare the effect of anticoagulants with antiplatelet agents, for secondary prevention, in people with NRAF and previous cerebral ischemia. Search methods We searched the Cochrane Stroke Group trials register (last searched 9 June 2003) and contacted trialists. Selection criteria Randomised trials comparing oral anticoagulants with antiplatelet agents in patients with NRAF and a previous TIA or minor ischemic stroke. Data collection and analysis Both reviewers extracted and analysed data. Main results Two trial were identified. The European Atrial Fibrillation Trial (EAFT) involving 455 patients, who received either anticoagulants (International Normalised Ratio (INR) 2.5 to 4.0), or aspirin (300 mg/day). Patients joined the trial within three months of transient ischemic attack or minor stroke. The mean follow up was 2.3 years. In the Studio Italiano Fibrillazione Atriale (SIFA) trial, 916 patients with NRAF and a TIA or minor stroke within the previous 15 days were randomised to open label anticoagulants (INR 2.0 to 3.5) or indobufen (a reversible platelet cyclooxygenase inhibitor, 100 or 200 mg BID). The follow-up period was one year. The combined results show that anticoagulants were significantly more effective than antiplatelet therapy both for all vascular events (Peto odds ratio (Peto OR) 0.67, 95% confidence interval (CI) 0.50 to 0.91) and for recurrent stroke (Peto OR 0.49, 95% CI 0.33 to 0.72). Major extracranial bleeding complications occurred more often in patients on anticoagulants (Peto OR 5.16, 95% CI 2.08 to 12.83), but the absolute difference was small (2.8% per year versus 0.9% per year in EAFT and 0.9% per year versus 0% in SIFA). Warfarin did not cause a significant increase of intracranial bleeds. Authors' conclusions The evidence from two trials suggests that anticoagulant therapy is superior to antiplatelet therapy for the prevention of stroke in people with NRAF and recent non-disabling stroke or TIA. The risk of extracranial bleeding was higher with anticoagulant therapy than with antiplatelet therapy.

A direct and stereospecific method was worked out to quantify indobufen enantiomers in human serum using capillary zone electrophoresis (CZE). The indobufen enantiomers and (+)- S -ketoprofen (internal standard, IS) were separated in a fused silica capillary, filled with heptakis 2,3,6-tri- O -methyl-β-cyclodextrin as a chiral selector in a buffer of pH 5.0. Indobufen enantiomers and other non-steroidal anti-inflammatory drugs: flurbiprofen, ketoprofen and (+)- S -naproxen were also separated during one analytical run. UV absorbances of indobufen enantiomers were measured at 282 nm. Influence of temperature on resolution of the enantiomers, and the electrophoretic parameters: electrophoretic ( μ ep ) and electroosmotic ( μ EOF ) mobilities were also determined. Validation of the method was carried out. Calibration curves of indobufen enantiomers were linear in the range of 0.2–20.0 μg/ml. Percent recovery of both enantiomers from acidified serum was calculated after extraction with methylene chloride. Intra- and inter-day measurement precision and accuracy were below 15.0%. Limits of quantitation and detection were also estimated. The elaborated method was tested in vivo after administration of a single dose of 200 mg rac -indobufen tablets to healthy volunteers. Calculated parameters confirmed usefulness of the method in human pharmacokinetic studies on indobufen enantiomers. The direct CZE method can provide an alternative to HPLC, where enantiomers used to be derivatised before determination.

This is an outcomes pharmacodynamic study using Nonsteroidal antiinflammatory agents, particularly acetylsalicylic acid (ASA), have been shown useful in various cardiovascular disorders, but they can be a major cause of iatrogenic gastrointestinal injury. Newer NSAIDs such as indobufen, an inhibitor of platelet aggregation that acts by reversibly inhibiting the platelet cyclooxygenase enzyme, have proven to be as effective as the older NSAIDs and appear to have a better gastrointestinal tolerability profile. When the gastroduodenal tolerability of 10 days of oral treatment with indobufen or ASA was assessed in healthy adult volunteers using endoscopic evaluation and the modified score scale of Lanza, only 1 of 18 (6%) volunteers who received indobufen had an increased erosion score at the completion of therapy, compared with 6 of 18 volunteers who received ASA (33%). Overall, both drugs were well tolerated. These results suggest that indobufen has a lower incidence of gastrointestinal effects than other NSAIDs and should be useful in the management of patients with cardiovascular disease.

The binding of the enantiomers of indobufen (INDB) to human serum proteins was investigated using the racemic mixture or the pure (+)-S-enantiomer in a concentration range of 2.5–100.0 mg/L. In addition, the pharmacokinetics of free (unbound) and total INDB enantiomers were studied 1) following administration of a single 200 mg rac-INDB tablet to healthy volunteers, and 2) in obliterative atherosclerosis patients at steady state. The free fraction of INDB was obtained by ultrafiltration. Using the racemic mixture, the binding parameters of the two enantiomers were different, showing enantioselectivity in protein binding. The (−)-R-enantiomer was bound more strongly to human serum albumin, with association constant K = 11.95 ± 0.98 × 105 M−1 and n = 0.72 ± 0.02 binding sites. The comparable data for the (+)-S-enantiomer were K = 4.65 ± 0.02 × 105 M−1, n = 0.92 ± 0.01. When the binding of (+)-S-enantiomer was studied alone, the association constant K (2.10 ± 0.18 × 105 M−1) was lower and the number of binding sites was increased, to n = 1.87 ± 0.17. Competition occurred between the enantiomers, with the (−)-R-enantiomer displacing its antipode. The fraction of both enantiomers bound to serum proteins was 99.0%, which increased with decreasing initial concentration of the enantiomers. In healthy volunteers the (+)-S-enantiomer was eliminated faster than its (−)-R antipode, resulting in a lower AUC for the (+)-S-enantiomer. Significant differences were observed in the total INDB enantiomer concentrations. The mean unbound fraction of (−)-R- and (+)-S-INDB was 0.45% and 0.43%, respectively. Levels of the free (+)-S-enantiomer were higher than its (−)-R-antipode at steady state in patients with obliterative atherosclerosis who also took other drugs. The free enantiomer fraction increased to around 1% upon repeated administration. We conclude that the more rapid elimination of the (+)-S enantiomer is associated with its weaker binding to serum proteins. Chirality 14:736–741, 2002. © 2002 Wiley-Liss, Inc.

The excretion balance and the urinary metabolism of indobufen (+/- 2-[p-(1-oxo-2-isoindolinyl)-phenyl] butyric acid), a platelet aggregation inhibitor, has been studied in rats and mice after oral administration. The urinary metabolic profile of indobufen exhibited a marked species difference. The major metabolic pathway in the mouse was acyl glucuronidation followed by renal excretion, whereas in rats, 5-hydroxylation and subsequent sulphation at the introduced hydroxyl group predominated. Comparison of these results with previous data obtained in humans indicates that the mouse, and not the rat, is the rodent species of choice to be considered in the study of this compound.

UNLABELLED Indobufen inhibits platelet aggregation by reversibly inhibiting the platelet cyclooxygenase enzyme thereby suppressing thromboxane synthesis. Clinical trials have evaluated the efficacy of oral indobufen in the secondary prevention of thromboembolic complications in patients with or without atrial fibrillation, in the prevention of graft occlusion after coronary artery bypass graft (CABG) surgery and in the treatment of intermittent claudication. In the secondary prevention of thromboembolic events indobufen 200 mg once or twice daily was significantly more effective than no treatment although not as effective as ticlopidine 250 mg once or twice daily, during 1-year nonblind clinical trials. Compared with placebo, indobufen 100 mg twice daily significantly reduced the risk of stroke in a small 28-month trial of patients at increased risk of systemic embolism (50% had atrial fibrillation). Furthermore, in patients with nonrheumatic atrial fibrillation and a recent cerebrovascular event enrolled in the 1-year Studio Italiano Fibrillazione Atriale (SIFA) trial, indobufen 100 or 200 mg twice daily was as effective as warfarin (titrated to produce an international normalised ratio of 2.0 to 3.5) in the secondary prevention of thromboembolic events; the incidences of the composite end-point of major vascular events (10.6 vs 9.0%) and recurrent stroke (5 vs 4%) were similar between treatments. In 2 large 12-month trials, the Studio Indobufene nel Bypass Aortocoronarico (SINBA) and the UK study, indobufen 200 mg twice daily was as effective as aspirin (acetylsalicylic acid) 300 or 325 mg plus dipyridamole 75 mg 3 times daily in the prevention of early and late occlusion of saphenous grafts in patients after CABG surgery. Indobufen 200 mg twice daily for 6 months significantly improved walking capacity compared with placebo, and caused a more pronounced improvement in both pain-free and total walking distance than either pentoxifylline 300 mg or aspirin 500 mg twice daily in separate 6- and 12-month studies of patients with intermittent claudication. Oral indobufen up to 200 mg twice daily was generally well tolerated in >5000 patients with atherosclerotic disease. Adverse events (predominantly gastrointestinal), reported by 3.9% of patients, rarely required withdrawal from treatment. In the SINBA and UK studies, fewer adverse events and less gastrointestinal bleeding were seen with indobufen than with aspirin plus dipyridamole treatment, while in the SIFA trial, noncerebral bleeding events occurred significantly less frequently in indobufen than warfarin recipients (0.6 vs 5.1%) and major bleeding events occurred only in the warfarin group. CONCLUSION Indobufen is as effective as warfarin in the prophylaxis of thromboembolic events in at risk patients with nonrheumatic atrial fibrillation, as aspirin plus dipyridamole in the prevention of CABG occlusion and may be more effective than aspirin or pentoxifylline in improving walking capacity in patients with intermittent claudication. The improved tolerability profile of indobufen (favourable gastric tolerance and reduced haemorrhagic complications) compared with aspirin 300 to 325 mg 3 times daily or warfarin, in addition to a similar antiplatelet effect, suggests indobufen can be considered a drug with a definite role in the management of atherothrombotic events. In particular, indobufen may be an effective alternative for at risk patients with nonrheumatic atrial fibrillation in whom anticoagulant therapy is contraindicated or who are at higher risk of bleeding.

The plasma pharmacokinetics and urinary elimination of the enantiomers of indobufen (2-[p-(1-oxo-2-isoindolinyl)-phenyl]butyric acid), a novel platelet aggregation inhibitor, have been studied in male healthy volunteers given either the racemic compound or the S-enantiomer (200 mg racemate, 100 mg S-enantiomer). Enantiospecific analysis of indobufen in plasma and urine was achieved by HPLC of its L-leucinamide diastereoisomers. After administration of the racemate, the pharmacokinetic behaviour of the R- and S-enantiomers differed, the plasma levels of the S form declining more rapidly [half-lives = 6.2 hr (S), 8.7 hr (R)]. No substantial differences were observed in terms of plasma level profile of S-indobufen when administered alone and in the racemic mixture. A statistically significant difference between the two enantiomers after administration of the racemate was found in the area under the curve (AUC), peak plasma levels (Cmax) and elimination half-life (t1/2 beta) whereas no statistically significant difference was detected in the time of peak (tmax). When the pharmacokinetic parameters Cmax, AUC, t1/2 beta and tmax of S-indobufen administered alone or as racemate were compared, there were no statistically significant differences between treatments as well as between periods and sequences. The urinary excretion of total S-indobufen (free + glucuronide) and of total R-indobufen after administration of the racemate was essentially the same. No difference was observed either in the urinary excretion of total S-indobufen after administration of the racemate or of the S-enantiomer.

A rapid and selective liquid chromatography (LC) with solid phase extraction (SPE) to quantify indobufen (INDB) enantiomers is described. The INDB enantiomers and internal standard (racemic flurbiprofen) are extracted from a small volume of acidified serum (0.2 ml) by means of SPE using cartridges with octadecyl chemically bound phase and analysed on reversed phase (RP), C18 column with ultraviolet detection at 275 nm. Recovery of both INDB enantiomers was in the range 92.1-94.3%. The mobile phase is composed of acetonitrile-potassium dihydrogen phosphate (pH 4.75; 10 mM) (38:62, v/v). The linear range of the standards curves was from 0.25 to 25.00 microg ml(-1) in serum for both enantiomers. The limit of quantification and detection for both INDB enantiomers in serum were 0.25 microg ml(-1) (CV < or = 10%), and 0.1 microg ml(-1), respectively. Both intra- and inter-day accuracy and precision of the calibration curves were determined and their CV values did not exceed 10%. The validated method has been successfully applied for chiral pharmacokinetics studies of INDB from tablets and intramuscular injections in man.

The racemic compound indobufen and its (+)-and (—)-enantiomers have been compared for their effects on blood platelet function and rat carrageenan pleurisy. The antiplatelet properties were studied in-vitro in human platelets by measuring the inhibition of platelet aggregation and generation of serum thromboxane (Tx) B2. In-vivo, the antiplatelet and anti-inflammatory properties were studied in rats by measuring the inhibition of serum TxB2, the amount of 6-keto-PGF1α in pleural exudate and pleural exudate volume. In all tests the (+)-enantiomer was slightly more potent than the racemate, while the (—)-enantiomer was far less potent. In the same rats, treatment with the lowest doses of the compounds giving 90% inhibition of serum thromboxane B2 generation was associated with occasional macroscopic lesions of the gastric mucosa.

Two prospective, randomized, double-blind clinical trials, performed in the UK and Italy, showed that indobufen, a reversible cyclo-oxygenase inhibitor, is as effective as, and safer than, a combination of aspirin with dipyridamole in preventing occlusion of saphenous vein coronary artery bypass grafts (CABG) 1 year after surgery.To obtain, in a larger patient population, a more precise estimate of the possible differences in efficacy and safety between the two treatments.We performed a combined analysis of the results of the two studies, based on the 1-year angiography data, on a total of 934 patients with 2258 saphenous vein distal anastomoses.Patients in the UK and Italy had similar baseline clinical characteristics. The analysis confirmed that there were no significant differences between the two treatment groups in the proportion of patients with one or more occluded grafts and in the proportion of occluded distal anastomoses. The combined analysis showed that the difference in response frequency (indobufen compared with aspirin and dipyridamole) was close to 0: 2.0% (95% confidence interval (CI) -4.2 to 8.2) in terms of patients, and 0.8% (95% CI -2.5 to 4.2) in terms of distal anastomoses. The 1-year incidence of postoperative major cardiovascular events was not statistically different between the treatment groups (19/694 indobufen compared with 25/678 aspirin and dipyridamole).Two multicentre CABG studies performed in different countries in patients with similar characteristics showed similar results in terms of graft patency. On the basis of the combined analysis, the two treatments can reasonably be considered to be equally effective in the prevention of graft occlusion.