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Background: Ischemic stroke (IS) is a detrimental neurological disease and IS lacks valuable methods to recover body function. Indobufen (IND) could alleviate IS. However, the possible mechanism remains undefined. Methods: SH-SY5Y cells were cultured under the oxygen-glucose deprivation/reoxygenation (OGD/R) environment and then were treated with small interfering RNA (siRNA) of NRF2 and ATG5. The influence of various concentrations of IND (50 μM, 100 μM, 200 μM, and 400 μM) was determined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide. Levels of superoxide dismutase (SOD) and malonaldehyde (MDA) were examined by ELISA. Reactive oxygen species (ROS) production was determined by DCFH-DA staining. The protein levels of LC3II/LC3I, Beclin1, p62, NRF2, and ATG5 were detected by western blot. Results: IND increased cell viability, while depressed the rate of apoptosis in SH-SY5Y cells of OGD/R environment. IND inhibited autophagy by suppressing the levels of LC3II/LC3I, Beclin1 protein, and increasing p62 protein expression in SH-SY5Y cells of OGD/R environment. IND limited the contents of ROS and MDA, while amplifying the activity of SOD in SH-SY5Y cells with OGD/R exposure. IND also promoted NRF2 expression in OGD/R environment. Conclusion: IND could inhibit autophagy, oxidative stress, and apoptosis in SH-SY5Y cells with OGD/R exposure, further alleviating IS injury by regulating transcription factor NRF2 and inhibiting ATG5 expression. [ABSTRACT FROM AUTHOR]

Background: Indobufen is widely used in patients with aspirin intolerance in East Asia. The OPTION trial launched by our cardiac center examined the performance of indobufen based dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI). However, the vast majority of patients with acute coronary syndrome (ACS) and aspirin intolerance were excluded. We aimed to explore this question in a real-world population. Methods: Patients enrolled in the ASPIRATION registry were grouped according to the DAPT strategy that they received after PCI. The primary endpoints were major adverse cardiovascular and cerebrovascular events (MACCE) and Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding. Propensity score matching (PSM) was adopted for confounder adjustment. Results: A total of 7135 patients were reviewed. After one-year follow-up, the indobufen group was associated with the same risk of MACCE versus the aspirin group after PSM (6.5% vs. 6.5%, hazard ratio [HR] = 0.99, 95% confidence interval [CI] = 0.65 to 1.52, P = 0.978). However, BARC type 2, 3, or 5 bleeding was significantly reduced (3.0% vs. 11.9%, HR = 0.24, 95% CI = 0.15 to 0.40, P < 0.001). These results were generally consistent across different subgroups including aspirin intolerance, except that indobufen appeared to increase the risk of MACCE in patients with ACS. Conclusions: Indobufen shared the same risk of MACCE but a lower risk of bleeding after PCI versus aspirin from a real-world perspective. Due to the observational nature of the current analysis, future studies are still warranted to further evaluate the efficacy of indobufen based DAPT, especially in patients with ACS. Trial registration: Chinese Clinical Trial Register (https://www.chictr.org.cn); Number: ChiCTR2300067274. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate the efficacy and safety of indobufen in the prevention of venous thrombosis. METHODS: PubMed, Embase, the Cochrane Library, ClinicalTrial. gov, CNKI, Wanfang Data and CBM were searched electronically for randomized controlled trial (RCT) of indobufen in the prevention of venous thrombosis (the interventions were indobuprofen alone or in combination with other conventional drugs, while the control measures were other positive control drugs alone or in combination with other conventional drugs) up to May 2023. Two reviewers independently screened literature according to the inclusion and exclusion criteria, extracted data, and assessed the methodological quality of the included literature. Meta-analysis was performed by using RevMan 5. 3 software. RESULTS: A total of 15 RCT with 2 164 patients were included. There were 1 117 patients in the indobufen group and 1 047 patients in the control group. Efficacy results showed that the there was sufficient evidence-based evidence for Meta-analysis of indobufen in thromboprophylaxis of atrial fibrillation (AF), thromboprophylaxis after major orthopedic surgery, and thromboprophylaxis of idiopathic model nephropathy, and the results were not worse than warfarin or other anticoagulants. In the prevention of thrombosis after AF combined with ischemic cardio-cerebrovascular disease, nephrotic syndrome and superficial varices of lower extremities, indobufen also had some evidence, yet it was not enough for quantitative analysis. Safety outcomes showed that the incidences of bleeding (RR = 0. 18,95% CI = 0. 09- 0. 38, P<0. 000 01) and minor bleeding (RR = 0. 17, 95% CI = 0. 05-0. 52, P = 0. 002) induced by indobufen in prevention of AF thrombosiswas were significantly lower than those in warfarin, with statistically significant differences. CONCLUSIONS: Indobufen has accumulated a certain amount of evidence-based evidence in the prevention of venous thrombosis. The clinical efficacy of indobufen in the prevention of venous thrombosis is not inferior to that of conventional therapy, and the safety of indobufen is better. [ABSTRACT FROM AUTHOR]

Currently, the standard treatment for patients who have undergone percutaneous coronary intervention (PCI) following acute myocardial infarction (MI) involves dual antiplatelet therapy (DAPT) with a combination of aspirin and a potent P2Y12 receptor inhibitor. However, the potential benefits of aspirin were partially constrained by the intolerance of some patients. The safety and efficacy of indobufen, an alternative antiplatelet agents to aspirin, in patients with AMI after PCI are yet to be thoroughly investigated. This retrospective study was conducted at a single center and utilized propensity score matching. The enrollment spanned from January 2019 to June 2022, incorporating patients with AMI after PCI. The participants were categorized into two groups based on discharged prescriptions: the aspirin DAPT group and the indobufen DAPT group. The primary endpoint focused on net adverse clinical event (NACE), defined as a composite outcome, including cardiac death, recurrence of MI, definite or probable stent thrombosis (ST), target lesion revascularization (TLR), ischemic stroke and Bleeding Academic Research Consortium (BARC) criteria type 2, 3, or 5. All the patients underwent a one-year follow-up period. A total of 1451 patients were enrolled in this study, with 258 assigned to the indobufen DAPT group and 1193 to the aspirin DAPT group. Following 1:1 propensity score matching, 224 patients were retained in each group. In the indobufen DAPT group, 58 individuals (25.9%) experienced the primary endpoint within one year, compared to 52 individuals (23.2%) in the aspirin DAPT group (HR 1.128, 95% CI 0.776-1.639, p = .527). Specifically, no significant differences were observed in either the efficacy endpoint (MACCE, 20.1% vs. 14.7%, HR 1.392, 95% CI 0.893-2.170, p = .146) or the safety endpoint (BARC 2,3 or 5, 8.04% vs. 10.30%, HR 0.779, p = .427). These findings remained consistent at 1, 3, or 6 months. Additionally, the incidence of gastrointestinal symptoms were significantly lower in indobufen DAPT group compared to the aspirin DAPT group (7.1% vs. 14.3%, p = .022). Our research reveals that the efficacy and safety of indobufen are comparable to aspirin in Chinese patients with AMI following PCI. Given the potential advantages of indobufen in alleviating gastrointestinal symptoms, we propose it as a viable alternative for individuals intolerant to aspirin. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate the cost-effectiveness of indobufen combined with ticagrelor versus aspirin combined with ticagrelor for antiplatelet therapy after percutaneous coronary intervention (PCI). METHODS: Markov model was used to simulate the economic outcomes of patients treated with indobufen + ticagrelor and aspirin + ticagrelor for antiplatelet therapy after PCI. Quality-adjusted life years (QALY) was set as the effectiveness measure, the total costs, total effectiveness and incremental cost-effectiveness ratios ( ICER) of two treatment regimens were calculated. RESULTS: Over a 10-year time horizon, the total cost of indobufen + ticagrelor was 172 292. 28 yuan, while the total cost of aspirin + ticagrelor was 169 950. 51 yuan. The QALY gained with indobufen + ticagrelor and aspirin + ticagrelor were 6. 540 and 6. 335, respectively. The ICER of indobufen + ticagrelor to aspirin + ticagrelor was 11 472. 09 yuan / QALY, lower than per capita GDP in China. These results suggested that indobufen+ticagrelor is significantly better than aspirin+ticagrelor in cost-effectiveness. Sensitivity analysis demonstrated that the results of the study were robust and reliable. CONCLUSIONS: Results of the study indicate that indobufen + ticagrelor is more cost-effectiveness than aspirin + ticagrelor under the current economic conditions in China, and can be used as the first selection of antiplatelet therapy for patients after PCI. [ABSTRACT FROM AUTHOR]

Commonly, most oral non-steroidal anti-inflammatory drugs (NSAIDs) have known gastric adverse reactions due to their long-term and high dose administration. In this study, a novel liquid sustained-release system based on multiple-unit in situ hydrogel beads was designed to address this issue. The system is composed of sodium alginate (SA), gellan gum (GG), zinc oxide (ZnO), and magnesium oxide (MgO). Furthermore, indobufen was loaded into the system to evaluate its gastric mucosal protection effect. This effect can be attributed to the topical antacid, pepsin inhibition, and sustained drug release properties of the system. It was proven that the stored solid gel system could undergo a "solid to liquid" transition after shaking. Once swallowed, the liquid gel could disperse well in the stomach as hydrogel beads. Then, the "liquid to solid" gelation occurred from the exterior to interior of each multiple-unit gel bead, triggered by the release of Zn2+ and Mg2+ from neutralization reactions. The formed gel demonstrated mild antacid effect that lasted for 3 hours and 66.3% pepsin inhibition in vivo. Moreover, the rats treated with the indobufen gel system showed a drug plasma concentration versus time curve with less fluctuation compared to the rats treated with the marketed preparation (YinDuo®) group. The gel system also exhibited an extended T max (6.50 hours) and reduced C max (52.87 μg/mL). Additionally, the gastric mucosal protection of the gel system was verified using three types of peptic gastric ulcer models. These findings suggested that this multiple-unit in situ gel could be a potential oral liquid sustained release delivery system for NSAIDs. [ABSTRACT FROM AUTHOR]

The risk of thromboembolic events is elevated in patients with nephrotic syndrome, and warfarin use has been associated with an increased risk of bleeding. Indobufen, a selective cyclooxygenase-1 inhibitor, is currently being evaluated for the prevention of thromboembolic events in nephrotic syndrome. This study aimed to compare the efficacy and safety of indobufen with that of warfarin in patients with nephrotic syndrome. This multicenter, randomized, three-arm, open-label, parallel controlled trial involved a total of 180 adult patients with nephrotic syndrome from four centers in China. Patients were randomly assigned to receive 100 mg indobufen (bid), 200 mg indobufen (bid), and 3 mg warfarin (qd) daily for 12 weeks. The primary endpoints included thromboembolic and bleeding events, while laboratory results and adverse events constituted secondary endpoints. No thromboembolic events occurred in the high-/low-dose indobufen and warfarin groups. Moreover, the use of a low dose of indobufen significantly reduced the risk of minor bleeding events compared with warfarin use (2% versus 18%, p <.05). Finally, adverse events were more frequent in warfarin-treated patients. This study found that indobufen therapy provided equivalent effects in preventing thromboembolic events compared with warfarin therapy, while low dose of indobufen was associated with a reduced risk of bleeding events, thus it should be recommended for the prevention of thromboembolic events in clinical practice in patients with nephrotic syndrome. ChiCTR-IPR-17013428. [ABSTRACT FROM AUTHOR]

After the reaction, the solid was collected by removing the solvent, and the pure compound B 6 b was obtained through washing with dilute hydrochloric acid. The compounds methyl 2-(4-nitrophenyl)butanoate ( B 7 b ), [25] methyl 2-(4-aminophenyl)butanoate ( B 5 b ), [26] methyl 2-(4-(1-oxoisoindolin-2-yl)phenyl)butanoate ( B 6 b ), [24] and 2-(4-(1-oxoisoindolin-2-yl)phenyl)butanoic acid (indobufen), [27] were synthesized in accordance with the methods published. Keywords: indobufen; anticoagulant; diludine; isoindolinone; hectogram-scale EN indobufen anticoagulant diludine isoindolinone hectogram-scale 2543 2546 4 07/31/23 20230817 NES 230817 Graph Isoindolinone is an important structural motif of many natural products [2] and synthetic drugs [5] that exhibit important biological activities such as the anti-inflammatory drug indobufen, the anti-tumor agent lenalidomide, the tumor necrosis factor (TNF- ) production inhibitor DWP205190, and selective metabotropic glutamate receptor (mGluR) 1 allosteric antagonist CFMTI (Figure 1). 2-(4-(1-Oxoisoindolin-2-yl)phenyl)butanoic Acid (Indobufen) To a solution of compound B 6 b (296.7 g, 0.959 mol) were added MeOH (1500 mL) and aq 1 N NaOH (1500 mL). [Extracted from the article]

Clinically, indobufen is widely used for the treatment of antiplatelet aggregation and anticoagulation. Prior studies have discovered that abnormal platelet function can be promptly restored to normal when the drug is stopped. Herein, through the study of the enzyme reaction kinetics, we demonstrated that the inhibitory effect of indobufen on cyclooxygenase-1 (COX-1) was reversible and non-competitive. Specifically, the cyclooxygenase inhibition experiment showed that the level of 6-keto-PGF1α in the gastric mucosa of the indobufen-treated groups was significantly higher than that of the aspirin group (###p < 0.001), indicating a higher level of PGI2 in and a better physiological state of the gastric mucosa. Moreover, the rat gastric ulcer index and mucosal section experiments further confirmed the relief of gastrointestinal irritation and the adverse reaction rate of the indobufen-treated group compared to those of the aspirin group. Furthermore, indobufen was verified to exert reversible inhibitory activity on the heme group of COX-1 and thus reversibly inhibit COX-1 activity. In general, compared with aspirin, the long-term oral administration of indobufen yields a lower risk of gastrointestinal symptoms, such as ulcers. [ABSTRACT FROM AUTHOR]

Objective To investigate the effects of indobufen combined with clopidogrel on vascular endo- thelial function, inflammatory factors, and oxidative stress in patients with acute coronary syndrome. Methods This study retrospectively selected 156 patients as the research object who had acute coronary syndrome and underwent PCI in our hospital from June 2020 to March 2022. They were divided into two groups by the number table method, with78 patients in each group. The observation group was treated with indobufen combined with clopidogrel, and the control group was treated with clopidogrel. The efficacy and indicators of patients were compared, and the adverse reactions were recorded. Result The therapeutic effect of the observation group was better than that of the control group (P < 0.05); After treatment, the endothelial function indicators of both groups of patients were significantly improved compared to before treatment (P < 0.05), and the VEGF level in the observation group was higher than that in the control group (P < 0.05), while ET-1 was lower than that in the control group (P < 0.05); After treatment, the inflammatory factors in patients decreased compared to those after treatment (P < 0.05), and the observation group showed hs CRP and TNF-α levels. These levels were significantly lower than those of the control group (P < 0.05); After treatment, the oxidative stress indicators of patients improved compared to before treatment (P < 0.05), and the NO and tNOS indicators in the observation group were significantly higher than those in the control group (P < 0.05), while the malondialdehyde levels were lower than those in the control group (P < 0.05); The incidence of cardiovascular adverse events and bleeding in the observation group after treatment was lower than that in the control group (P < 0.05); There was no statistically significant difference in the incidence of adverse reactions between the two groups (P > 0.05). Conclusion The application of indobufen combined with clopidogrel in the treatment of acute coronary syndrome patients has a definite therapeutic effect that can effectively improve various indicators, reduce the incidence of adverse events, and alleviate inflammation and therefore lead to a low bleeding rate, and good safety, which is worthy of further promotion. [ABSTRACT FROM AUTHOR]

Clinical trials are the most effective method for evaluating the efficacy and safety of new drugs or new therapies, and can provide high-quality evidence-based medical evidence. In recent years, the number of clinical trials worldwide increased gradually, negative results from clinical trials are very common. When the main result of a clinical trial is negative, it does not necessarily mean that the study is a failure, and researchers should consider multiple factors to find potential benefits. Therefore, we elaborated in detail the 12 key points to consider, when encountering the negative primary outcome, and discussed by taking indobufen versus aspirin in acute ischemic stroke (INSURE) study as an example provide reference experience for subsequent clinical research design and results interpretation. [ABSTRACT FROM AUTHOR]

Background: Dual antiplatelet therapy (DAPT) with aspirin as a background therapy has become the standard care following percutaneous coronary intervention (PCI). However, some adverse non-cardiac effects limited the use of aspirin in clinical practice. Thus, evaluation of pharmacological alternatives to aspirin is attractive. Previous data indicated that indobufen could lessen the unwanted side effects of aspirin while retain the antithrombotic efficacy, but its combination with a P2Y12 inhibitor is still lack of randomized clinical trial (RCT) evidence. Methods: In this randomized, open-label, non-inferiority trial, patients with negative cardiac troponin undergoing coronary drug-eluting stent (DES) implantation were randomly assigned in a 1:1 ratio to receive either indobufen-based DAPT (indobufen 100mg twice a day plus clopidogrel 75mg/d for 12 months) or conventional DAPT (aspirin 100mg/d plus clopidogrel 75mg/d for 12 months). The primary endpoint was a 1-year composite of cardiovascular (CV) death, nonfatal myocardial infarction (MI), ischemic stroke, definite or probable stent thrombosis (ST), or Bleeding Academic Research Consortium (BARC) criteria type 2, 3 or 5 bleeding. The endpoints were adjudicated by an independent Clinical Event Committee. Results: Between January 11, 2018 and October 12, 2020, 4551 patients were randomized in 103 cardiovascular centers: 2258 patients to the indobufen-based DAPT group and 2293 to the conventional DAPT group. The primary endpoint occurred in 101 (4.47%) patients in the indobufen-based DAPT group and 140 (6.11%) patients in the conventional DAPT group (absolute difference -1.63%, pnon-inferiority <0.001; hazard ratio (HR) 0.73, 95% CI 0.56 to 0.94, p=0.015). CV death, nonfatal MI, ischemic stroke and ST were observed in 0.13%, 0.40%, 0.80%, and 0.22% of patients in the indobufen-based DAPT group, and 0.17%, 0.44%, 0.83%, and 0.17% of patients in the conventional DAPT group (all p>0.05). The occurrence of BARC criteria type 2, 3 or 5 bleeding events was lower in the indobufen-based DAPT group compared to the conventional DAPT group (2.97% vs 4.71%, HR 0.63, 95%CI 0.46 to 0.85, p=0.002), with main decrease in type 2 bleeding (1.68% vs 3.49%, HR 0.48, 95%CI 0.33 to 0.70, p<0.001). Conclusions: In Chinese patients with negative cardiac troponin undergoing DES implantation, indobufen plus clopidogrel DAPT compared with aspirin plus clopidogrel DAPT significantly reduced the risk of 1-year net clinical outcomes, which was mainly driven by a reduction in bleeding events without an increase in ischemic events. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to investigate the pharmacodynamic effects of indobufen and low-dose aspirin in patients with coronary atherosclerosis. Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

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-naïve healthy subjects, generating 892 samples containing randomly selected concentrations of the drugs of 0-128 mg/L. Collageninduced 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 Rindobufen 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

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 (μep) and electroosmotic (μEOF) 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. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]